What is Fabry disease?
The body continuously performs metabolic processes which produce, recycle and remove vital compounds. In patients with Fabry disease one such common compound formed of three sugars and a fatty substance (globotriaosylceramide) does not get broken down due to the missing or non-functioning enzyme alpha galactosidase A. Since this fatty compound (lipid) is not being broken down and removed, it begins to accumulate. Thus, Fabry disease is often referred to as a “storage disorder” due to this abnormal accumulation. In patients with Fabry disease, this accumulation occurs primarily in the blood and in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels. This abnormal process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.
Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys.
How common is Fabry disease?
Fabry disease affects an estimated 1 in 40,000 to 60,000 males. This disorder also occurs in females, although less frequently. Milder, late-onset forms of the disorder are probably more common than the classic, severe form.
What genes are related to Fabry disease?
An inherited disorder, Fabry disease is caused by mutations in the GLA gene. This gene provides instructions for making an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures that serve as recycling centers within cells. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease.
GLA gene mutations that result in an absence of alpha-galactosidase A activity lead to the classic, severe form of Fabry disease. Mutations that decrease but do not eliminate the enzyme’s activity usually cause the milder, late-onset forms of Fabry disease that affect only the heart or kidneys.
How do people inherit Fabry disease?
This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the GLA gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all.
Unlike other X-linked disorders, Fabry disease causes significant medical problems in many females who have one altered copy of the GLA gene. These women may experience many of the classic features of the disorder, including nervous system abnormalities, kidney problems, chronic pain, and fatigue. They also have an increased risk of developing high blood pressure, heart disease, stroke, and kidney failure. The signs and symptoms of Fabry disease usually begin later in life and are milder in females than in their affected male relatives. Some females who carry a mutation in one copy of the GLA gene never develop any of the signs and symptoms of Fabry disease.
All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.
Typically, the disease begins in childhood with episodes of pain and burning sensations in the hands and feet. In addition, young patients often develop a spotted, dark red skin rash (angiokeratomas) seen most densely from the umbilicus to the knees, a decreased ability to perspire, and a characteristic change on the cornea of the eye which does not affect vision. The painful episodes may be brought on by exercise, fever, fatigue, stress, or change in weather conditions.
The disease is slowly progressive and symptoms of kidney, heart and/or neurologic involvement usually occur between the ages of 30 to 45. Many patients are first diagnosed when the accumulated storage material begins to affect kidney or heart function. Therefore, it is important to annually monitor kidney function by blood and urine tests because kidney disease is a major complication that can occur in affected males.
A common heart symptom in Fabry patients is mitral valve prolapse, which is a benign condition that is present in approximately 10% of the normal population. More serious, but rarer, complications of Fabry disease include heart disease and strokes.
Other symptoms may include varying degrees of abdominal discomfort, frequent bowel movements shortly after eating, joint pain, back pain primarily in the kidney region or ringing of the ears (tinnitus).
Females may show a wide range of clinical manifestations. Some individuals remain completely asymptomatic and have normal levels of a gal a while some are as severely affected as hemizygous males. This variability is most likely to be caused by random inactivation of one copy of the X-chromosome in each cell. The most common symptom of Fabry disease seen in heterozygous females is corneal dystrophy, which occurs in around 70% of females. Other symptoms that have been reported in females with Fabry disease include: angiokeratomas, acroparesthesias, anhidrosis, gastrointestinal disturbances, vascular lesions in the conjunctiva and retina, kidney disease, autonomic and other neurological complications such as tinnitus and vertigo, cardiovascular abnormalities, cerebrovascular abnormalities, fatigue. Women may often be misdiagnosed as having lupus or other conditions.
Although the signs and symptoms of Fabry disease generally appear during childhood, the diagnosis may often be missed. The earliest symptoms of Fabry disease in children are usually pain and angiokeratomas. The pain may, however, be dismissed as ‘growing pains’, while angiokeratomas may be overlooked during a routine clinical examination, particularly if they are confined to locations such as the backs of the ears. Cardiac and renal involvement can also begin in childhood, thus early diagnosis and careful monitoring are necessary. Other symptoms include Hypohidrosis (inability to sweat), GI symptoms that mimic chronic inflammatory bowel disease, recurrent nausea and vomiting, vertigo, tinnitus, headaches, fevers.
Pain associated with Fabry disease can be difficult to treat but usually responds to medications such as Tegretol (carbamazepine), Dilantin or Neurotin. Metoclopramide, Lipisorb (a nutritional supplement), Pancrelipase may be beneficial in treating Gastrointestinal hyperactivity. Early experiments with enzyme replacement therapy indicate promising results.
Enzyme replacement therapy is available to help reduce the amount of fatty GL3 build-up in the body’s tissues and prevent irreversible damage to organs. Reglan is often used to help alleviate the stomach and intestinal issues associated with Fabry disease.