Fabry disease (also known as alpha-galactosidase-A deficiency) is an inherited neurological disorder that occurs when the enzyme alpha-galactosidase-A cannot efficiently break down fatty materials known as lipids into smaller components that provide energy to the body. The mutated gene allows lipids to build up to harmful levels in the body's autonomic nervous system (the part of the nervous system that controls involuntary functions such as breathing and heartbeat), as well as in the eyes, kidneys, and cardiovascular system.

Males are primarily affected, although a milder and more variable form is common in females. Onset of symptoms is usually during childhood or adolescence. Neurological signs include:

• Burning pain in the arms and legs, which worsens in hot weather or following exercise
• The buildup of excess material in the clear layers of the cornea (resulting in clouding but no change in vision)
• Impaired circulation that may lead to stroke or heart attack due to fatty storage in blood vessel walls

Other symptoms include:

• Heart enlargement
• Progressive kidney impairment leading to renal failure
• Gastrointestinal difficulties
• Decreased sweating
• Fever
• Angiokeratomas (small, non-cancerous, reddish-purple elevated spots on the skin) may develop on the lower part of the trunk of the body and become more numerous with age

Enzyme replacement can reduce lipid storage, ease pain, and preserve organ function in some people with Fabry disease. Drugs are often prescribed to treat pain and gastrointestinal distress that accompanies Fabry disease but do not treat the disease. The U.S. Food and Drug Administration (FDA) has approved migalastat (Galafold) as an oral medication for adults with Fabry disease who have a certain genetic mutation. Anti-platelet medications can help prevent strokes and medications that lower blood pressure can slow the decline of kidney function in people with Fabry disease. Some individuals may require kidney transplants or dialysis.

Fabry disease is a type of lysosomal storage disease. Lysosomes are round structures found in the cells of the body that are full of special proteins called enzymes. Lysosomal enzymes help breakdown other proteins, carbohydrates, fats, and other substances. In Fabry disease, there is not enough of the enzyme alpha-galactosidase (alpha-GAL). Alpha-GAL helps breakdown a fatty acid called "globotriaosylceramide" or GL3 ". Without enough alpha-GAL, the lysosomes become filled with GL-3 and can not work well. Symptoms of Fabry disease may include episodes of pain, especially in the hands and feet, clusters of small, dark red spots on the skin called angiokeratomas, a decreased ability to sweat (hypohidrosis), cloudiness of the front part of the eye (corneal opacity), and hearing loss. Internal organs, such as the kidney, heart or brain, may also be affected, leading to progressive kidney damage, heart attacks, and strokes. Milder forms of Fabry disease may appear later in life and affect only the heart or kidneys.

Fabry disease is caused by certain changes (pathogenic variants, also called mutations) in the GLA gene. Since the GLA gene is located on the X chromosome, Fabry disease is inherited in an X-linked manner.

Although an enzyme assay test measuring the activity of alpha-GAL can diagnose Fabry disease in males, diagnosis is usually made by genetic testing in both males and females. Treatment may include enzyme replacement therapy (ERT), pain medications, and ACE inhibitors. End stage kidney disease may be treated by dialysis or kidney transplantation. Migalastat (brand name Galafold) received FDA approval in 2018 to treat some adults who have specific pathogenic variants (mutations) causing Fabry disease.

Fabry disease is caused by variants (also known as mutations) in the GLA gene. This gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. Variants in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease.

GLA gene variants that result in an absence of alpha-galactosidase A activity lead to the classic, severe form of Fabry disease. Variants that decrease but do not eliminate the enzyme's activity usually cause the milder, late-onset forms of Fabry disease that typically affect only the heart, kidneys, or blood vessels in the brain.

Normal Function

The GLA gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that act as recycling centers within cells. Lysosomes use digestive enzymes to process worn-out cell components and recycle usable parts.

Alpha-galactosidase A breaks down a molecule called globotriaosylceramide, which consists of three sugars attached to a fatty substance. This molecule is degraded as part of the normal recycling of old red blood cells (erythrocytes) and other types of cells.

Health Conditions Related to Genetic Changes

Fabry disease

More than 370 mutations in the GLA gene have been identified in people with Fabry disease. Most of these genetic changes are unique to single families. The most common type of mutation changes a single protein building block (amino acid) in alpha-galactosidase A. Other mutations delete part of the GLA gene, insert extra genetic material into the gene, or insert a premature stop signal in the gene's instructions for making alpha-galactosidase A. Alterations in the GLA gene produce an abnormal version of the enzyme that is unable to break down globotriaosylceramide effectively. As a result, this substance builds up in the body's cells, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of globotriaosylceramide damages these cells, leading to the varied signs and symptoms of Fabry disease.

Mutations that eliminate the activity of the alpha-galactosidase A enzyme lead to the severe, classic form of Fabry disease, which typically begins in childhood. Mutations that reduce but do not completely eliminate the enzyme's activity usually cause milder, late-onset forms of the disorder.

Other Names for This Gene

• AGAL_HUMAN
• Agalsidase alfa
• Alpha-D-galactosidase A
• alpha-D-galactoside galactohydrolase
• Alpha-galactosidase
• alpha-Galactosidase A
• ceramidetrihexosidase
• GALA
• galactosidase, alpha
• Melibiase

Genomic Location

Fabry disease is inherited in an X-linked pattern, which means the genetic changes (pathogenic variants, also called mutations) that cause the disease occur in a gene (the GLA gene) on the X chromosome. Females have two X chromosomes and therefore have two copies of the GLA gene. Males have one X chromosome and one Y chromosome, and therefore have only one copy of the GLA gene.

In males, a pathogenic variant in the GLA gene is enough to cause symptoms of Fabry disease, because there is not another working copy of the gene. Females with a pathogenic variant in one copy of the gene can be seemingly asymptomatic, can have severe symptoms, or anything in between. A high percentage of females who have a pathogenic variant experience significant symptoms.

When a female with a GLA pathogenic variant (with or without symptoms) has children, each child (male or female) has a 50% chance to inherit the GLA pathogenic variant because each child will inherit one of her X chromosomes at random.

When a male with a GLA pathogenic variant has children, the pathogenic variant will be passed on to all of his daughters, and to none of his sons. Therefore, a male cannot inherit the disease from his father.

Signs of Fabry disease in boys usually don’t appear until late infancy to early childhood. Girls with Fabry disease may also have signs and symptoms of the disease, but they are usually less severe and happen at a later age than boys.

Early signs of the condition may include the following:

• Pain in hands and feet, especially with fever or exercise
• Decreased or absent sweating (hypohidrosis)
• Small, raised dark red spots on skin (angiokeratomas)
• Digestive problems, like diarrhea
• Cloudiness in the eyes that doesn’t affect vision
• Nausea or vomiting
• Heart problems

If your baby has Fabry disease, it is possible that other family members may have Fabry disease as well. Signs of Fabry disease in adults include the following:

• Early heart disease (including early heart attack and heart failure)
• Kidney failure, typically starting with high protein in urine
• Early strokes

Newborn screening for Fabry disease requires collecting a small amount of blood from your baby’s heel. Screening measures how much alpha-Gal A is in your baby’s blood. Babies with a low level of this enzyme might have Fabry disease.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Fabry disease is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood or urine tests
• DNA testing using a blood or cheek swab sample

You should complete any recommended follow-up testing as soon as possible. Children with this condition can have serious health problems if they are not diagnosed quickly. It is important for the whole family to know if a baby has Fabry disease because other family members may need immediate treatment.

False-positive newborn screening results for this condition may happen. Some babies with positive newborn screening results for Fabry disease have “pseudodeficiency.” Pseudodeficiency means that a baby’s enzyme levels are low on the screening but are normal in their body. These babies do not have and will never develop Fabry disease.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

Management of Fabry disease may include treatment of specific symptoms, as well as medications to prevent or slow the development of secondary complications.

• Phenytoin, carbamazepine, or gabapentin may be used for episodes of severe burning pain in the hands and feet (acroparesthesias).

• ACE inhibitors may be used to treat decreased kidney function (renal insufficiency). ACE inhibitors can reduce the loss of protein in the urine (proteinuria). If kidney function continues to decrease dialysis and/or kidney transplantation may be necessary. A kidney transplanted successfully into a person with Fabry disease will remain free of the harmful build up of the fatty acid GL3 and therefore will restore normal kidney function. However it will not stop the buildup of GL3 in other organs or systems of the body. In addition, all potential donors that are relatives of the a person with known Fabry disease should have their genetic status checked to make sure they do not have a pathogenic variant (mutation) in the GLA gene (even if they do not have symptoms).

• Enzyme replacement therapy (ERT), human α-Gal A enzyme, may be used to improve symptoms associated with Fabry disease and to stabilize organ function. Studies however suggest ERT may only slightly improve long term outcomes.

• Migalastat (Galafold) may also be used to treat certain people with Fabry disease. It works by increasing the activity of the enzyme alpha-GAL, so is different than enzyme replacement therapy (ERT). Migalastat is approved by the United States Food and Drug Administration (FDA) for adults and adolescents 16 years of age and older, with a confirmed diagnosis of Fabry disease and a pathogenic variant (mutation) in the GLA gene that produces an alpha-GAL enzyme that responds to the treatment. About 35 and 50% of the people diagnosed with Fabry may be helped by migalastat. Migalastat has been approved by similar agencies in Europe, Israel, Australia, and Canada, and is registered for approval in other countries.

• Medications may be given to control blood pressure and to lower cholesterol levels. Aspirin and similar medications may be recommended to prevent a heart attack.

People with Fabry disease should be seen annually, or more frequently, by a doctor familiar with managing Fabry disease to check the function of their kidneys and heart. Hearing should also be checked annually. Brain imaging is recommended every 2 years. A person with Fabry disease may need a team of specialists in addition to their primary care doctor or pediatrician and genetic specialist, including, depending on symptoms, neurologists, cardiologists (heart doctor), nephrologists (kidney doctor), ophthalmologists (eye doctor), otorhinolaryngologists (ear, nose, and throat doctor), and others.

To prevent other complications, medications can be given to control blood pressure and medications to lower cholesterol, and the use of aspirin and similar medications is recommended to prevent heart attack.

For individuals with kidney problems, a low protein diet may be recommended. Support from friends and family can help with the emotional difficulties, such as depression, that are often seen in individuals with a chronic illness. Pain management is also an issue for many individuals with Fabry disease. Avoidance of strenuous activity, stress, sun exposure, and temperature extremes can help reduce the frequency and severity of pain. Drinking more water in hot weather and during physical activity can minimize the likelihood of heat exhaustion. Individuals with Fabry disease may also wish to avoid smoking, as it can make lung symptoms worse.

Can Fabry disease continue to affect the kidneys after a transplant?

While after a kidney transplant, Fabry disease continues to affect the rest of the body, it does not affect the transplanted kidney(s). The transplanted kidney is not susceptible to deposition of glycosphingolipids (the fatty substance that builds up in the bodies of affected individuals) because the normal α-Gal A enzyme activity in the donor tissue breaks down the glycosphingolipid substrates within the kidney. Therefore, successful kidney transplantation restores the function of the kidney(s).

Should enzyme replacement therapy (ERT) for Fabry disease be continued after a kidney transplant?

Although the residual enzyme in a donor kidney will prevent GL3 from building up in the transplanted kidney, it cannot prevent GL3 from building up in the other cells of the body. Because of this, it has been recommended that individuals affected with Fabry disease continue ERT to prevent accumulation of GL3 in their the heart, blood vessels, and other cells of the body. A pilot clinical trial studying the use of ERT in three kidney transplant patients with Fabry disease and severe cardiac involvement did strongly suggest that non-kidney related complications are improved after starting ERT and that ERT was safe for these individuals. Therefore, ERT may still be useful in managing some of the other symptoms associated with Fabry disease.

How might Fabry disease be managed after a kidney transplant?

Because Fabry disease involves multiple organs, it is still important to manage the disease after an affected individual has had a kidney transplant. Although the donor kidney is not susceptible to glycosphingolipid deposition, other parts of the body are still susceptible to damage. Management for individuals affected by Fabry disease after a kidney transplant may still include:

• Enzyme replacement therapy (ERT) - ERT has been associated with benefit in clinical trials, including improvement of cardiac structure and function, reduction in severity of neuropathic pain, and improvement in gastrointestinal involvement in addition to stabilization of kidney function
• Treatment for acroparesthesias
• Prevention of complications such as ischemic heart disease and cerebrovascular disease
• Surveillance including renal function studies, yearly cardiology evaluation, and yearly hearing evaluation

The recommended post-transplant care may affect an individual's treatment options for Fabry disease. Individuals interested in learning about the best treatment regime for themselves or family members should consult with health care providers who specialize in Fabry disease and kidney transplantation; a multi-disciplinary approach may be necessary.

Fabry disease affects an estimated 1 in 1,000 to 9,000 people. Milder, late-onset forms of the disorder are probably more common than the classic, severe form.