Fabry disease
Fabry disease is an inherited genetic disorder characterized by a deficiency in the enzyme alpha-galactosidase A, resulting from mutations in the GLA gene located on the X chromosome. This condition leads to the accumulation of fatty deposits, particularly globotriaosylceramide, in various organs, impacting blood flow and causing damage over time. While males who inherit the defective gene typically present with significant symptoms, females can be carriers and may experience a range of symptoms, from none to severe. Common symptoms include pain in the extremities, skin lesions, and complications related to the heart and kidneys. Diagnosis often involves a combination of clinical evaluation and specific enzyme or genetic testing. Although there is no cure for Fabry disease, treatment options like enzyme replacement therapy (Fabrazyme) can help manage symptoms and slow disease progression. Ongoing research aims to improve treatment strategies, particularly for children. Genetic counseling can be beneficial for families with a history of the disorder, as there are no preventive measures available.
Fabry disease
ALSO KNOWN AS: Alpha-galactosidase A deficiency; Anderson-Fabry disease; angiokeratoma corporis diffusum; angiokeratoma diffuse; ceramide trihexosidase deficiency; gla deficiency; glycolipid lipidosis; hereditary dystopic lipidosis
DEFINITION Fabry disease is an inherited genetic disorder caused by a defective gene. The disease causes fatty deposits in several organs of the body.
Males who inherit the defective gene will express the disease. Females who have a single copy of the gene are called carriers and most are asymptomatic (do not have symptoms). However, some women do have symptoms, and the severity of these symptoms can vary widely. On occasion, women may be as severely affected as men.
Risk Factors
The primary risk factor for Fabry disease is having family members who have the disease or are carriers of the disease.
Etiology and Genetics
Fabry disease results from a mutation in the GLA gene, located on the long arm of the X chromosome at position Xq22. This gene encodes a protein called alpha-galactosidase A, which normally breaks down a fatty metabolic intermediate known as globotriaosylceramide. When the gene is missing or mutated, the enzyme function is absent or severely reduced, and as a result globotriaosylceramide will build up in cells over time. The endothelial cells lining the blood vessels in the heart, kidney, and nervous system are particularly prone to this fatty accumulation, and the consequent damage to these cells reduces blood flow to the organs.
The inheritance pattern of Fabry disease is typical of all sex-linked recessive mutations (those found on the X chromosome). Mothers who carry the mutated gene on one of their two X chromosomes face a 50 percent chance of transmitting this disease to each of their male children. Female children have a 50 percent chance of inheriting the gene and becoming carriers like their mothers. Affected males will pass the mutation on to all of their daughters but none of their sons. Female carriers with one mutant and one normal copy of the gene often exhibit a mild form of the disease, although there is considerable variability in the degree of expression, and some carriers remain totally asymptomatic. The severe classic form of the disease is found almost exclusively in males.
Symptoms
Symptoms of Fabry disease may begin in childhood or early adulthood. Common symptoms include pain and burning sensations in the hands and feet, often provoked by exercise, fatigue, or fever; spotted, dark red skin lesions (angiokeratomas) that generally are found in the area between the belly button and the knees (they may also be found elsewhere); inability to sweat; and changes in the eyes, such as corneal opacities and cataracts.
As adults, males may experience symptoms due to blood vessel blockage, including kidney problems, often requiring dialysis or transplant; risk of early stroke or heart attack; chest pain; hypertension; heart failure, left ventricular hypertrophy; mitral valve prolapse or insufficiency; frequent bowel movements after eating; and diarrhea. Additional symptoms in adult males due to heart vessel blockage may include joint or back pain, ringing in the ears (tinnitus) or dizziness (vertigo), chronic bronchitis or shortness of breath, osteoporosis, delayed puberty or retarded growth, and stroke.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Diagnosis is usually made on the basis of the symptoms listed above. A test to measure the enzyme GALA or a DNA analysis can confirm Fabry disease.
Treatment and Therapy
There is no cure for Fabry disease. However, in 2003, the US Food and Drug Administration (FDA) approved the use of Fabrazyme (recombinant alpha-galactosidase), an enzyme replacement therapy, as treatment for Fabry disease. Treatment, which involves intravenous infusion every two weeks, was recommended for all adults with Fabry disease and for all adult women who are known carriers. In 2020 results of a long-term clinical study found a significant benefit of treatment. Preliminary pediatric data is somewhat encouraging, but enzyme replacement in children is still an experimental procedure. The National Institutes of Health (NIH) is conducting ongoing research into the use of Fabrazyme in children.
Replagal (agalsidase alfa) can also be used to treat the disease and was approved for use in Europe in 2001. However, though the manufacturers applied for FDA approval for the drug, they withdrew their application in 2012 when the FDA required further clinical trials, claiming that it would take too much time and effort to conduct these tests for a drug which had already been used successfully for years. Therefore, Fabrazyme remains the only treatment for Fabry disease available in the United States.
In 2024, it was announced that a new enzyme replacement therapy, or ERT, designed to treat Fabry disease would begin clinical trials. This ERT stabilizes the alpha-Gal A protein that breaks down the Gb3 fatty molecules and preventing them from forming toxic accumulations. The clinical trials were slated to begin in 2025.
Medications or procedures are used to treat symptoms of Fabry disease, including carbamazepine (Tegretol), which is used to treat pain. According to the FDA, patients of Asian ancestry who have a certain gene, called HLA-B*1502, and take carbamazepine are at risk for dangerous or even fatal skin reactions. The FDA recommends that patients of Asian descent get tested for this gene before taking carbamazepine. Patients who have been taking this medication for a few months with no skin reaction are at low risk of developing these reactions. Patients should talk to their doctors before stopping this medication.
Other medications used to treat the pain of Fabry disease are Dilantin (phenytoin) and Neurontin (gabapentin). Lipisorb, the brand name for a nutritional supplement with medium chain triglyceride (MCT); Reglan (metoclopramide); and Cotazym (pancrelipase) treat stomach hyperactivity. Anticoagulants can be used to treat certain heart disorders, and hemodialysis and kidney transplantation can treat kidney disease.
Prevention and Outcomes
There is no known way to prevent Fabry disease. Individuals who have Fabry disease or have a family history of the disorder can talk to a genetic counselor when deciding to have children.
Bibliography
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Khan, A., et al. "Lentivirus-Mediated Gene Therapy for Fabry Disease." Nature Communications, vol. 12, 25 Feb. 2021, DOI: 10.1038/s41467-021-21371-5. Accessed 30 Aug. 2024.
Khan, M. Gabriel. “Anderson-Fabry Disease.” Encyclopedia of Heart Diseases. Burlington: Elsevier, 2006. Print
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Lee, Brendan, and Fernando Scaglia. Inborn Errors of Metabolism: From Neonatal Screening to Metabolic Pathways. New York: Oxford UP, 2015. Print.
Lobo, Andrea. "Relay Plans Clinical Development of Fabry Disease Treatment." Fabry Disease News, 14 June 2024, fabrydiseasenews.com/news/relay-plans-clinical-development-fabry-disease-treatment/. Accessed 30 Aug. 2024.
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Waldek, Stephen, et al. “Life Expectancy and Cause of Death in Males and Females with Fabry Disease: Findings from the Fabry Registry.” Genetics in Medicine 11.11 (2009): 790–96. Print.