Fabry disease is a lysosomal storage disorder caused by a deficiency of the alpha-galactosidase A enzyme, primarily affecting males due to its X-linked recessive nature.
There are two forms of Fabry disease. The classic form, observed in males, often starts in childhood or adolescence and includes signs like dark skin patches (angiokeratomas) and severe pain in extremities (acroparesthesia). Altered sweating and eye changes are common, while hearing loss, gastrointestinal issues, and pulmonary complications may also occur. Renal insufficiency, cardiac problems, and cerebrovascular disease are major causes of mortality, with kidney function deteriorating over time, leading to end-stage renal disease (ESRD) in adulthood. Cardiac manifestations include hypertension, angina, arrhythmia, heart attack, and heart failure, while cerebrovascular disease may present as strokes or transient ischemic attacks (TIA). In atypical forms, most classic symptoms are absent, with only heart or kidney involvement later in life. Higher levels of alpha-galactosidase A activity in these individuals lead to this distinct presentation. There is evidence that enzyme replacement therapy (ERT) may prevent some primary manifestations of Fabry disease and it is typically recommended for all affected males (including children) and for some female carriers.
Fabry disease is caused by pathogenic (disease-causing) variants in the GLA gene on the X chromosome and exhibits X-linked recessive inheritance. This means that one pathogenic variant is enough to cause the disease in both males (who have one X chromosome and one Y chromosome) and females (who have two X chromosomes) may experience symptoms depending on how many copies of the X chromosome that has the pathogenic variant are turned on in the cells.
Female carriers may be asymptomatic or may exhibit symptoms ranging from mild to severe. However, in most cases, symptoms tend to be milder with onset being later in life than in their affected male relatives.
Other names for this condition are alpha-galactosidase A deficiency, Anderson-Fabry disease, angiokeratoma corporis diffusum, angiokeratoma diffuse, ceramide trihexosidase deficiency, GLA deficiency, and hereditary dystopic lipidosis.