What is Fabry disease?
Fabry disease is a rare, X-linked recessive lysosomal storage disorder, seen in all ethnic groups, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-GAL). Partial or complete deficiency of alpha-GAL leads to progressive accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in visceral tissues and the vascular endothelium throughout the body.
The inability to breakdown GL-3 leads to progressive damage to the kidney, heart and nervous system. The clinical course of Fabry disease is usually marked by chronic pain, angiokeratomas, hypohidrosis, heat and cold intolerance, corneal opacities, renal failure, stroke and cardiac complications. As the disease progresses, complications may become life threatening.
What are the different types of Fabry disease?
Growing evidence indicates there may be a significant number of "atypical variants" - hemizygotes who have few or none of the hallmark symptoms of classical Fabry disease.
Atypical variants have residual plasma alpha-GAL levels (1% to 30% of normal) and present much later in life than patients with classical Fabry disease. They are often identified by chance and usually have manifestations predominately in one organ system.
What are the risk factors for Fabry disease?
Since Fabry is X-linked, the disease predominantly affects males (hemizygotes), who have little, if any, endogenous alpha-GAL. Although an X-linked recessive disease, females with Fabry often experience varying degrees of disease manifestations. It is inherited through the mother who, with each conception, has a 50% chance of passing the defective gene on to all offspring. Sons who inherit the gene will have Fabry disease. Daughters who inherit the mutated Fabry gene will be carriers. Because of X-chromosomal inactivation, some female carriers develop symptoms of mild, moderate or classical Fabry disease. Males with Fabry disease pass on the defective gene to none of their sons and all of their daughters.
Although a positive family history is a strong indicator for Fabry disease, de novo or spontaneous mutations have been documented.
What causes Fabry disease?
Deposition of the stored glycosphingolipid (Gb3) in visceral organs (kidneys, heart and nervous system, including the central, peripheral and autonomic nervous system). Although storage occurs in many cell types it is most prevalent in the vascular endothelium throughout the body.
What are the symptoms for Fabry disease?
The cardinal presenting features of Fabry disease are intermittent acroparesthesia and episodic crises of pain and fever (especially in childhood), angiokeratomas, hypohidrosis, heat and cold intolerance and a characteristic "whorled" corneal opacity that does not affect vision. There can be significant proteinuria and renal failure, hypertrophic cardiomyopathy or cardiac arrythmias and/or early TIA or stroke.
The list below provides an overview of the signs and symptoms of Fabry disease that may be seen at different stages of life.
Other Fabry-related cerebrovascular signs and symptoms associated with Fabry disease may include:
How is Fabry disease diagnosed?
Clinical heterogeneity and the rarity of Fabry disease make the diagnosis of Fabry disease a challenge. The age of presentation, presenting symptoms and clinical course vary from individual to individual. One confounding factor in diagnosis is the fact that many common signs and symptoms of Fabry disease are common in other conditions.
Definitive diagnosis can be made by testing for deficient alpha-GAL enzyme activity in plasma, leukocytes, tears or biopsied tissue in males. Because female heterozygote enzyme levels can fall in the normal range, they are nondiagnostic in females.
DNA mutational analysis is required for diagnosis in females. In both males and females, mutational analysis is helpful in familial genetic risk assessment.
Fabry disease can be diagnosed prenatally by chorionic villus sampling (at 9–10 weeks) and amniocentesis (at approximately 16 weeks).
Current Treatments in Fabry Disease
Disease management strategies may include medications and lifestyle approaches to symptom relief and interventions to delay serious sequelae due to organ damage (e.g. kidney transplantation, cardiac pacemaker insertion).
Treatment of Fabry disease includes management of symptoms and of life-threatening complications. Because the disease affects multiple organ systems, a multidisciplinary team approach to management may be necessary (geneticist, genetic counselor, gastroenterologist, nephrologist, neurologist, dermatologist, ophthalmologist, cardiologist, pediatrician).
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