Fabry Disease

Fabry disease is a rare inherited condition where a specific type of fat builds up in your body’s cells because you lack a crucial enzyme to break it down. This buildup can affect many organs including your heart, kidneys, and nervous system, causing pain, organ damage, and potentially life-threatening complications.

Table of contents

• What is Fabry disease?
• Other names for this condition
• Types of Fabry disease
• What causes Fabry disease?
• How Fabry disease is inherited
• How common is Fabry disease?
• Signs and symptoms
• Organs affected by Fabry disease
• How is Fabry disease diagnosed?
• Treatment options
• Tests to monitor Fabry disease
• What to expect
• Living with Fabry disease

What is Fabry disease?

Fabry disease is a rare genetic condition in which your body doesn’t produce enough of a functioning enzyme called alpha-galactosidase A (alpha-GAL). This enzyme normally works inside structures called lysosomes within your cells, where it breaks down a fatty substance known as globotriaosylceramide (Gb3 or GL-3)^[1][3].

When you don’t have enough functioning alpha-GAL enzyme, this fatty substance cannot be broken down properly. As a result, Gb3 continues to accumulate in your cells and tissues throughout your body. This progressive buildup interferes with normal cell function and causes damage to various organs, particularly the blood vessels, kidneys, heart, brain, skin, and nervous system^[2][6].

Fabry disease is classified as a lysosomal storage disorder because it involves the abnormal storage of substances that should normally be broken down within lysosomes^[1].

Anderson-Fabry disease, Fabry’s disease, alpha-galactosidase A deficiency, angiokeratoma corporis diffusum, GLA deficiency

Other names for this condition

Fabry disease is also known by several other names, including Anderson-Fabry disease, alpha-galactosidase A deficiency, angiokeratoma corporis diffusum, and GLA deficiency^[1][3].

Types of Fabry disease

There are two main types of Fabry disease, which differ based on when symptoms first appear and how severe they are^[1][6]:

Classic type (Type 1): This form involves a complete or nearly complete absence of alpha-GAL enzyme activity. Symptoms typically begin in childhood or during the teenage years, sometimes as early as age 2. One of the earliest signs is often a painful burning sensation in the hands and feet. People with classic Fabry disease experience symptoms throughout their body, and these symptoms progressively worsen over time^[1][6].

Late-onset type (Type 2 or atypical): In this milder form, individuals have some residual enzyme activity, though it’s still lower than normal. Symptoms don’t appear until adulthood, typically when people are in their 30s or older. This type usually affects specific organs, most commonly the heart and kidneys, but doesn’t include the characteristic pain and skin rashes seen in the classic form. The first indication of late-onset Fabry disease may be kidney failure or heart disease^[1][6].

What causes Fabry disease?

Fabry disease is caused by changes (called mutations or variants) in the GLA gene. This gene provides instructions for making the alpha-galactosidase A enzyme. When the GLA gene is altered, it either prevents the production of the enzyme entirely or produces a version that doesn’t work properly^[3][10].

Researchers have identified hundreds of different mutations in the GLA gene that can cause Fabry disease. The type of mutation affects how severe the disease is. Mutations that result in no enzyme activity at all lead to the classic, severe form of Fabry disease. Mutations that allow some enzyme activity typically cause the milder, late-onset forms^[2][3].

How Fabry disease is inherited

Fabry disease is inherited in an X-linked pattern. This means the defective gene responsible for the condition is located on the X chromosome, one of the two chromosomes that determine biological sex. Males have one X chromosome and one Y chromosome, while females have two X chromosomes^[1][3].

How the disease is passed from parents to children depends on which parent has the faulty gene^[1]:

• Males with Fabry disease will pass the faulty X chromosome to all of their daughters, but none of their sons (because sons receive the Y chromosome from their father)
• Females with Fabry disease have a 50% chance of passing the affected X chromosome to each child, whether the child is male or female

Because males have only one X chromosome, a single altered copy of the GLA gene is sufficient to cause the condition. Males typically experience more severe symptoms than females. Females, who have two X chromosomes, usually have less severe symptoms because they also have one normal copy of the gene. However, many females with one altered copy of the GLA gene do experience significant medical problems, including nervous system abnormalities, kidney problems, chronic pain, fatigue, and an increased risk of heart disease, stroke, and kidney failure. Some females may have symptoms as severe as those seen in affected males, while a small percentage may never develop symptoms at all^[3][7].

How common is Fabry disease?

Fabry disease is rare, but estimates of how common it is vary depending on the population studied and which forms of the disease are included. Classic Fabry disease affects approximately 1 in 40,000 to 1 in 117,000 males^[1][2].

Late-onset or atypical forms of Fabry disease appear to be more common. Some studies suggest these forms may affect about 1 in 1,500 to 1 in 4,000 males, and potentially as many as 1 in 1,000 to 1 in 9,000 people when both males and females are included^[1][2][3].

Experts aren’t certain how many women have Fabry disease because some women don’t have symptoms or have mild symptoms that are easy to dismiss, so the condition often goes undiagnosed in females^[1]. The disease affects all racial and ethnic groups^[2].

Signs and symptoms

The symptoms of Fabry disease vary widely between individuals and depend on which type you have and which organs are affected. Symptoms can range from relatively mild to life-threatening^[5][8].

Early symptoms that often appear in childhood include^[1][6]:

• Episodes of pain, particularly a burning, tingling, or prickling sensation in the hands and feet (called acroparesthesias)
• Severe, debilitating episodes of intense, burning pain (called Fabry crises) that may be accompanied by fever, fatigue, and body aches
• Small, dark red or purple spots on the skin (called angiokeratomas), typically appearing between the belly button and knees
• Reduced ability to sweat or not sweating at all (hypohidrosis or anhidrosis)
• Intolerance to heat or cold
• A whorl-like pattern in the clear front part of the eye (called cornea verticillata), which doesn’t affect vision and can only be seen during a specialized eye examination
• Gastrointestinal problems, including stomach pain, nausea, vomiting, cramping, diarrhea, or constipation, and pain or bloating after eating

As the disease progresses, additional symptoms may develop^[1][4][6]:

• Feeling constantly tired or drained (fatigue)
• Headaches and dizziness, including vertigo
• Ringing in the ears (tinnitus) and hearing loss
• Protein in the urine (proteinuria), which may cause foamy-looking urine
• Blood in the urine
• More frequent or urgent urination
• Swelling (edema) in the legs, ankles, or feet
• Muscle cramps

Men typically have more severe symptoms than women, though women can also experience serious complications^[1][8].

Organs affected by Fabry disease

As Fabry disease progresses, the buildup of fatty substances can cause serious problems in several major organs^[4][5]:

Heart: Fabry disease can cause an abnormal thickening of the heart muscle (hypertrophy), making the heart stiff and unable to relax properly. This can lead to irregular heartbeats, heart valve problems, shortness of breath, chest pain, and heart failure. Some people may experience a fast-beating, fluttering, or pounding heartbeat^[4][5].

Kidneys: Kidney complications are common and serious. The accumulation of fatty substances in kidney cells can lead to progressive kidney damage. Protein in the urine is often the first sign of kidney involvement. Without treatment, chronic kidney disease may worsen, potentially leading to end-stage kidney failure. This typically occurs in the third or fourth decade of life and is a common cause of death in people with Fabry disease^[2][4].

Brain and nervous system: The buildup of fatty substances in blood vessels can increase the risk of stroke or transient ischemic attacks (mini-strokes). Damage to peripheral nerve fibers that transmit pain signals causes the characteristic burning pain in the hands and feet. Neurological complications may include sudden numbness or weakness, confusion, trouble speaking, vision problems, difficulty walking, dizziness, loss of balance, or severe headaches^[2][5].

Lungs: Some people experience breathing problems such as wheezing, shortness of breath, dry cough, and reduced lung function^[7].

How is Fabry disease diagnosed?

Diagnosing Fabry disease can be challenging and may take a long time because its symptoms are common to many other illnesses and can affect so many different parts of the body. Many people see several different doctors for various symptoms before receiving the correct diagnosis^[8].

The diagnostic process typically begins with a physical examination and a review of your medical history and symptoms. Your doctor will ask about your family history, as Fabry disease runs in families^[5][8].

To confirm the diagnosis, doctors use^[1][5]:

Blood test for enzyme activity: This test measures the level of alpha-galactosidase A activity in your blood. In males with Fabry disease, enzyme activity is very low or absent. This test is reliable for diagnosing males, but may be less definitive for females because they can have variable enzyme levels^[5].

Genetic testing (DNA test): This test looks for mutations in the GLA gene. Genetic testing is particularly important for diagnosing females with Fabry disease and for identifying specific gene variants. If your family history suggests you could be at risk, your doctor may recommend genetic testing^[5][8].

Imaging tests: Various imaging studies can help doctors understand which organs are affected and assess the extent of damage. These may include magnetic resonance imaging (MRI), computed tomography (CT) scans, echocardiograms to examine the heart, or kidney ultrasounds. An MRI or CT scan can look for areas of the brain that show signs of stroke or neurological damage^[5].

Urine tests: Tests that check for protein or blood in the urine can be an early sign of kidney involvement^[6].

Eye examination: A specialized eye exam using a slit lamp can detect the characteristic corneal changes seen in Fabry disease^[1].

Treatment options

There is no cure for Fabry disease, but treatments can help manage symptoms, slow disease progression, and prevent serious complications^[8][11].

Treatments targeting the enzyme deficiency

Enzyme replacement therapy (ERT): This is a primary treatment for Fabry disease. It involves regular intravenous infusions of synthetic alpha-galactosidase A enzyme to replace the deficient enzyme in your body. The FDA-approved enzyme replacement therapy is agalsidase beta (Fabrazyme). You receive this treatment through an IV infusion, typically every two weeks. Some patients may receive infusions more frequently, such as every 10 to 11 days, depending on their condition^[11][15].

The replacement enzyme helps break down the accumulated fatty substances, preventing further buildup. The goal is to prevent progression of organ damage and early death, as well as improve quality of life. Males with classic Fabry disease may be advised to start treatment right away after diagnosis, even if they don’t have symptoms yet, because organ damage may have already begun. Females usually need treatment if they show symptoms or laboratory signs of organ damage^[11].

Enzyme replacement therapy can cause side effects such as shivering or fever. Your doctor can give you an antihistamine to help prevent these reactions^[11].

Oral chaperone therapy: A newer medication called migalastat (Galafold) was approved by the FDA in 2018. This is a pill you take by mouth that helps the alpha-galactosidase A enzyme your body produces work better. It’s slightly less expensive and more convenient than IV infusions. However, it only works for people with certain specific gene mutations. Your doctor needs to test you to determine if you have one of the mutations that respond to this medication. Fewer than half of people with Fabry disease have a mutation that responds to this treatment^[11][14].

Treatments for specific symptoms

In addition to treatments that address the underlying enzyme deficiency, doctors prescribe medications to manage specific symptoms and complications^[11]:

• Pain medications: Anti-seizure medicines such as carbamazepine, gabapentin, or phenytoin may be prescribed to treat the severe burning pain in the hands and feet
• Blood pressure medications: ACE inhibitors can help control high blood pressure and also protect the kidneys, lowering the chance that you may need dialysis or a kidney transplant
• Heart medications: Various medications may be needed to treat irregular heartbeats or other heart problems
• Gastrointestinal medications: These can help with vomiting, diarrhea, constipation, nausea, and other digestive problems
• Skin treatments: A dermatologist can remove dilated blood vessels on the skin during an office visit
• Hearing aids: These may help with tinnitus, dizziness, or hearing loss

Advanced treatments

For people with advanced organ damage, more intensive treatments may be necessary^[17]:

• Dialysis or kidney transplant for kidney failure
• Heart transplant for severe heart disease
• Medications and interventions to prevent or treat stroke

Tests to monitor Fabry disease

Because Fabry disease affects your whole body and symptoms tend to get more severe as you age, regular health screenings are essential. You may need these tests at least once a year, and more often if you have complications such as kidney disease or heart disease^[11]:

• Blood tests: These check your white and red blood cell counts, electrolytes, and how well your kidneys and liver are working
• Urine tests: These look for blood or protein in your urine, which can be early signs of kidney disease
• Electrocardiogram (ECG or EKG): This records the electrical signals in your heart to check for unusual heart rhythms
• Echocardiogram: This uses sound waves to create images of your heart and assess its structure and function
• Kidney function tests: These measure how well your kidneys are filtering waste from your blood
• Brain imaging: MRI or CT scans may be done periodically to check for signs of stroke or other neurological problems

What to expect

Fabry disease is progressive, meaning it gradually gets worse over time. However, the rate of progression varies widely from person to person. This is especially true for women, who typically experience more variable disease courses than men^[17].

Men with classic Fabry disease usually develop serious medical problems starting around ages 30 to 45. For women, complications may not appear until their 50s or much later. Children with Fabry disease generally do well with proper medical care^[17].

In late-onset Fabry disease, symptoms don’t begin in childhood. Instead, doctors might first notice heart or kidney problems starting in a person’s 30s^[17].

As people age, Fabry disease can lead to life-threatening complications, including heart disease, stroke, kidney disease, and kidney failure. These problems are usually milder in women than in men, but women can also have severe symptoms. Both males and females may develop an enlarged heart, heart valve problems, irregular heartbeats, heart attacks, strokes, and kidney failure^[17].

Many people with Fabry disease live full and productive lives, especially with early diagnosis and treatment. However, without treatment, males in particular have a shorter life expectancy than the general population. The usual causes of shortened lifespan are heart disease or kidney disease. If doctors find and treat these problems early, it may help extend life expectancy^[17].

Treatment with enzyme replacement therapy or oral chaperone therapy can significantly improve symptoms and help people feel better day to day. Men and women with Fabry disease are living longer and healthier lives than ever before, thanks to advances in treatment^[17].

Living with Fabry disease

Living with Fabry disease requires ongoing management and lifestyle adjustments. Beyond medical treatments, there are several important steps you can take to stay as healthy as possible^[15]:

Adhere to your treatment schedule: Taking your treatments consistently as prescribed is crucial. For those receiving enzyme replacement therapy, this means regular infusions every two weeks or as recommended by your doctor^[15].

Stay well hydrated: Drinking adequate fluids is important for kidney health^[15].

Maintain a healthy lifestyle: Eating a balanced, kidney-friendly diet, staying physically active (as your symptoms allow), managing your weight, getting adequate sleep, and controlling blood pressure and cholesterol can all help slow disease progression and improve overall health^[15].

Manage swelling: If you experience swelling in your lower legs, compression socks may help^[15].

Keep all medical appointments: Regular checkups and monitoring tests are essential to catch complications early^[11].

Address mental health: Living with Fabry disease isn’t just about physical symptoms. The condition can have a significant impact on your mental health and well-being, potentially leading to increased risk of anxiety, depression, and panic attacks. The disease may affect your relationships and cause feelings of isolation, loneliness, or guilt about having a genetic disease that can be passed to children. It’s important to seek support from mental health professionals, family, friends, and support groups^[16].

Connect with others: Joining a support group or connecting with others who have Fabry disease can help you feel less alone. Your doctor can put you in touch with support resources, or you can contact organizations such as the Fabry International Network or the National Fabry Disease Foundation^[8][17].

Talk to your healthcare team: Keep your doctors informed about any new or worsening symptoms. If you experience symptoms of a heart attack (such as chest pain, shortness of breath, or pain spreading to the arms, back, or jaw) or stroke (such as sudden numbness, confusion, trouble speaking, vision problems, difficulty walking, or severe headache), seek emergency medical care immediately^[5].

• Heart
• Kidneys
• Brain
• Central nervous system
• Skin
• Eyes
• Gastrointestinal system
• Blood vessels
• Ears
• Lungs