What is Fabry disease?
Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect which allows this to occur is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide.
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.
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the 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. Food and Drug Administration (FDA) approved treatment for Fabry has demonstrated positive results. Fabrazyme, Enzyme Replacement Therapy (ERT) was approved in 2003. In 2018 Galafold a pharmacological chaperone was approved by FDA.