Alpha-galactosidase A (alpha-GAL) is the enzyme deficient in Fabry disease. This leads to the buildup of fatty substances called lipids in the body’s cells, particularly in blood vessels, kidneys, and the heart. The condition can result in organ dysfunction and heart attacks, strokes, and kidney failure. Treatment options include enzyme replacement therapy and oral chaperone therapy to prevent complications. Fabry disease is passed from parents to their children and can affect various organs and systems in the body.
Types of Fabry disease
Fabry disease can be classified into two types based on the age of symptom onset:
Symptoms of classic Fabry disease appear during childhood or adolescence. These symptoms include a painful burning sensation in the hands and feet, skin rash (angiokeratomas), decreased sweating, gastrointestinal issues, and corneal dystrophy. Over time, the disease can progress to affect the heart and kidneys and lead to complications such as renal failure and heart problems. The average lifespan of males with the classic type was around 40 years before treatment options became available.
People with late-onset Fabry disease develop symptoms later in life, typically in their 30s or older. The initial signs may be related to kidney or heart problems. Individuals can experience varying degrees of symptom progression and severity.
Both types of Fabry disease result from the deficiency of the enzyme alpha-galactosidase A, leading to the accumulation of fatty substances in the body’s organs and tissues.
Symptoms of Fabry Disease
Fabry disease is a genetic condition characterized by the accumulation of fatty molecules in the body’s blood vessels and tissues. It primarily affects the heart, kidneys, skin, and nervous system. Females typically experience more severe symptoms than males, with the severity of symptoms varying by individual. Common signs and symptoms include:
Males may experience severe burning pain in the hands and feet, known as acroparesthesia. Exercise, fatigue, stress, or fever can trigger these episodes, which can last hours to days.
Anhidrosis or hypohidrosis
Decreased or absent sweat production (anhidrosis or hypohidrosis) can cause discomfort in warm temperatures, during exercise, or with fevers.
Reddish to dark-blue skin rash may appear, particularly between the hips and knees. These skin lesions can be flat or raised, commonly found in males with Fabry disease.
Abdominal cramping, frequent bowel movements, diarrhea, and reduced appetite may occur, especially after a large meal.
Abnormal deposits of glycolipids in the cornea can lead to a characteristic whorl-like opacity, visible through a slit-lamp examination by an ophthalmologist. Vision is typically unaffected.
Chronic fatigue, dizziness, headache, generalized weakness, nausea, vomiting, delayed puberty, sparse hair growth, joint malformations, and swelling in the feet and legs (lymphedema) may also be present.
Distinctive facial features include:
- A recessed forehead
- Fullness around the eye sockets
- Bushy eyebrows
- Coarse features
- Pronounced nose and ear lobules
- Thickened lips
- A prominent jaw
Pain, burning, and tingling are common symptoms of nervous system disorders. A “Fabry crisis” typically occurs in childhood or adolescence and is triggered by various factors.
Eye problems may include corneal abnormalities and twisted or slightly enlarged blood vessels in the eyes. These conditions do not usually affect vision but are essential for diagnosis and monitoring.
Skin abnormalities manifest as clusters of small, reddish, or dark-blue spots (angiokeratomas) on the skin, mainly between the belly button and knees. Broken blood capillaries, dry mouth, and sweating abnormalities are also standard.
Gastrointestinal symptoms may include diarrhea, abdominal cramping, frequent bowel movements, flatulence, reduced appetite, nausea, and vomiting.
Hearing problems like tinnitus, vertigo, and progressive or sudden hearing loss are frequently reported due to blood vessel narrowing and blockage.
Kidney impairment is a progressive aspect of the disease, leading to kidney failure in males with classic Fabry disease. Heart disease, cerebrovascular complications, respiratory problems, and other general symptoms such as delayed puberty, sparse hair growth, fatigue, and weakness may also occur.
Genetic Causes of Fabry Disease: Mutations in the GLA Gene on the X-Chromosome
Fabry disease is caused by alpha-galactosidase A (GLA) gene mutations on the X-chromosome. In females, one X-chromosome is randomly “turned off,” which can result in varying symptom severity. Males with the mutation will be affected. The GLA gene produces the α-Gal A enzyme that breaks down accumulating glycolipids in cells.
Over 965 mutations in the GLA gene have been reported, leading to different disease types and symptom variations. Type 1 classic subtype occurs with little enzyme activity, while type 2 later-onset subtype has residual activity. Both types result in the accumulation of glycolipids in tissues, especially in blood vessels, heart, and kidneys. Some GLA gene mutations are benign and do not cause Fabry disease. Learn more about biotechnology and genetic engineering
Preventing Fabry Disease
Participate in Clinical Trials to Drive Progress
Consider participating in clinical trials to advance the understanding and treatment of Fabry disease and related disorders. By volunteering for clinical research, you can help clinicians and scientists gain valuable insights into the disease and explore safer detection, treatment, and prevention methods.
Seeking Diverse Volunteers for Comprehensive Results
Researchers need volunteers of all backgrounds, including healthy individuals and those with an illness or disease, spanning different ages, sexes, races, and ethnicities, to ensure the applicability and effectiveness of study results.
Resources for Clinical Research Participation
For more information on participating in clinical research, visit NIH Clinical Research Trials and You or explore ongoing clinical trials for Fabry disease at Clinicaltrials.gov. If you carry the mutated gene for Fabry disease, consult a genetic counselor to understand the risk and explore options such as preimplantation genetic diagnosis (PGD) to ensure a healthy outcome.