Fabry disease is a genetic condition that affects the breakdown of certain fatty substances known as globotriaosylceramide (Gb3 or GL-3) due to a deficiency in the activity of an enzyme called alpha-galactosidase A. This deficiency is caused by a mutation in the GLA gene that provides instructions for this enzyme. As a result, these fatty substances build up within cells causing damage mainly to the heart and the kidneys.
Fabry disease in men and women
Fabry disease is inherited following an X-linked pattern, meaning the mutated gene that causes the disorder is carried on the X chromosome, one of the two sex chromosomes present in each cell. Men have one X chromosome and one Y chromosome, whereas women have two X chromosomes. Therefore, men may present more severe symptoms than women who usually have a healthy copy of the gene on their second X chromosome that can compensate for disease severity to a certain extent.
Types of Fabry disease
There are two main types of Fabry disease depending on when symptoms first appear: type 1, or classic Fabry disease, and type 2, or atypical late-onset Fabry disease, which can further be divided into cardiac and renal variants.
Men with type 1 Fabry disease have a residual or nonfunctional alpha-galactosidase A enzyme and develop symptoms of the disease at an early age. In contrast, the severity of symptoms in women is highly variable. Women with type 2 Fabry disease may not show any symptoms at all or may develop some symptoms only later in life.
Signs and symptoms of Fabry disease
Men with Fabry disease may have a characteristic facial appearance with a prominent brow bone and forehead and thickened lips.
Both men and women with Fabry disease may experience severe burning in the hands and feet caused by damage to the nerve cells. Men usually experience this earlier than women. These symptoms may be triggered by exercise, fatigue, stress, and fever, and may emerge as an ongoing sensation of burning and pain known as “Fabry crises.”
Abnormal deposits of fatty substances in the cornea, the transparent layer forming the front of the eye, and particularly in the walls of its blood vessel, result in what is known as corneal dystrophy. This does not usually affect vision.
Sweating abnormalities such as anhidrosis, absent sweat production, and hypohidrosis, diminished sweat production, may also occur and are more frequent in men with Fabry disease. Hyperhidrosis, excessive sweating, occurs less frequently.
Angiokeratomas are common in Fabry disease and consist of skin lesions characterized by a reddish or dark-blue rash. They are mainly found in the area between the belly button and the knees and become larger and more numerous with age. Even though angiokeratomas are not considered a biomarker to measure disease progression or even treatment outcomes, patients with this symptom are more likely to have major organ involvement.
Telangiectasia, or broken capillaries, is another common skin symptom and is often found on the face, lips, and mouth of Fabry disease patients.
Gastrointestinal symptoms such as abdominal cramping, frequent bowel movements, diarrhea, early satiety (feeling of fullness earlier than normal), reduced appetite, nausea, and/or vomiting may occur in patients with Fabry disease.
Kidney dysfunction results from a deposition of GL-3 in the kidneys and may advance to kidney failure especially in men with type 1 Fabry disease. These patients may need dialysis or a kidney transplantation by ages 35 to 45, whereas in women the prognosis is highly variable. In patients with type 2 Fabry disease, kidney involvement usually occurs around age 40 in men and may not occur at all in women.
Heart disease is caused by a deposition of GL-3 in heart tissues, including heart cells, nerve cells and blood vessels around the heart.
In men with type 1 Fabry disease, heart complications include arrhythmias; mitral insufficiency, or leakage of blood backward through the heart valve; left ventricular hypertrophy, the enlargement of the left ventricle of the heart whose role is to send oxygen-rich blood to all the body; and hypertrophic cardiomyopathy, excessive thickening of the heart muscle. Men with type 2 Fabry disease may develop the same symptoms, but they usually have a later onset.
Women with type 1 Fabry disease develop sinus bradycardia (a slower than normal heart rate), left ventricular hypertrophy, and hypertrophic cardiomyopathy. It is not clear whether women with type 2 Fabry disease develop heart disease.
Blood supply to the brain
A progressive deposition of GL-3 in the small blood vessels of the brain can result in cerebrovascular disease or a condition that affects blood supply to the brain. It typically occurs in type 1 Fabry disease and can result in a stroke.
Other general symptoms that may be associated with Fabry disease include delayed puberty, reduction in hair growth, malformation of the joints and fingers, lymphedema (swelling due to an accumulation of lymph in the feet and legs), chronic fatigue, dizziness, headache, and generalized weakness.
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