Fabry disease is a rare genetic lysosomal storage disorder characterized by an impaired ability to break down a specific type of fat known as globotriaosylceramide (Gb3 or GL-3). This results in the accumulation of GL-3 inside cells, which interferes with organ function and causes symptoms such as chronic pain, gastrointestinal problems, kidney dysfunction, and heart disease.
The two different kinds of Fabry disease, classic (also known as type 1) and non-classic/late-onset (also known as type 2), differ in disease severity and time of symptom onset.
Causes of classic Fabry disease
Fabry disease is caused by a mutation in the GLA gene, which provides the instructions necessary to build an enzyme called alpha-galactosidase. This enzyme is responsible for breaking down GL-3. Mutations in the GLA gene reduce the activity of the alpha-galactosidase enzyme, and results in a build-up of GL-3 within cells.
Different kinds of mutations can occur in the GLA gene and affect the activity of alpha-galactosidase differently. Some mutations result in very low activity levels (less than 3% of regular activity) while others allow the enzyme to preserve a higher level of activity (3%–15% of regular activity). Individuals with no or very low remaining enzyme activity develop classic or type 1 Fabry disease. Because GL-3 cannot be broken down, its deposits severely impact organ function.
In individuals with higher enzyme activity, less GL-3 builds up within cells, resulting in a milder form with a later onset. This is known as late-onset or type 2 Fabry disease.
Symptoms of classic Fabry disease
The first symptoms of classic Fabry disease typically appear in childhood or adolescence, and they worsen over time. The disease can affect many organs and cause a wide range of problems, which are summarized below.
Gastrointestinal problems such as diarrhea and constipation are among the first signs of classic Fabry disease.
Some individuals with classic Fabry disease have a decreased ability to sweat (anhidrosis). This may lead to problems with regulating body temperature, resulting in heat intolerance.
Acroparesthesia is the sensation of severe burning pain in hands and feet. It typically appears between the ages of 2 and 8 in patients with classic Fabry disease.
Kidney dysfunction is caused by the deposition of GL-3 in the kidneys, is more pronounced in patients with classic Fabry disease, and may progress toward kidney failure. Men with classic Fabry disease may need dialysis or kidney transplantation between the ages of 35 and 45. In women with classic Fabry disease, kidney involvement is more variable, and about 10%–15% of these patients develop kidney failure.
Men with classic Fabry disease develop arrhythmias, mitral valve regurgitation (where the heart’s mitral valve does not close tightly, leading to a backflow of blood to the heart), left ventricular hypertrophy (enlargement of the left ventricle of the heart), hypertrophic cardiomyopathy (thickening of the heart muscle), and heart failure. Women with classic Fabry disease show sinus bradycardia (a slower-than-normal heart rate), hypertrophic cardiomyopathy, and left ventricular hypertrophy.
GL-3 deposits that build up in the small blood vessels of the brain might affect the blood supply to the brain, which can result in a stroke.
GL-3 deposits in the lung may cause airway obstruction, and result in respiratory abnormalities in classic Fabry disease patients.
GL-3 accumulation in lymphatic vessels may cause lymphedema, which is characterized by swelling in the hands and feet. Individuals with classic Fabry disease may also experience frequent headaches, fatigue, and dizziness.
Last updated: Oct. 11, 2019
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