Fabry disease

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.

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.

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).

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.

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.

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.

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.

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.

The Fabry Registry supports research for Fabry disease by collecting information about patients with this diagnosis. You can join the registry to share your information with researchers and receive updates about participating in new research studies. Learn more about registries.

Ries, et al. Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics 2006;118:924-932.

Ries, et al. Pediatric Fabry Disease. Pediatrics 2005;115:e344-e355.

The National Fabry Disease Foundation offers information and support for Fabry disease. Click on the link to learn more.