Fabry disease

What is Fabry Disease?

Fabry disease is an inherited lysosomal storage disorder that is caused by harmful genetic changes (variants) in the GLA gene. The symptoms associated with Fabry disease are caused by a buildup of harmful substances in different organs and tissues of the body. Fabry disease is inherited in an X-linked manner. This means the condition is typically more severe in individuals assigned male at birth (XY). However, individuals assigned female at birth (XX) may also have symptoms of the condition. There is also both a classic and atypical form of this condition. The differences in presentation in this form are due to differences in the buildup of harmful substances in the body's tissues.

Classic Form

In the classic form of Fabry disease, symptoms usually begin in early childhood or adolescence. Patches of dark skin (angiokeratomas) are an early sign and most often appear on the lower half of the body. Other common symptoms include severe pain in the extremities (acroparesthesia); altered sweating (usually decreased sweating, aka hypohidrosis, but there are also reports of increased sweating, aka hyperhidrosis); and characteristic eye changes such as cloudiness in the cornea and/or lens (vision is typically not affected). Rarer symptoms include hearing loss and ringing in the ears (tinnitus); gastrointestinal issues; obstructive pulmonary disease such as chronic bronchitis or wheezing; and swelling (edema) in the lower extremities in adulthood.

Fabry disease symptoms that are a major cause of mortality are kidney disease, cardiac complications, and damage to the brain's blood vessels (cerebrovascular disease). Kidney function slowly deteriorates over time, with end-stage renal disease (ESRD) usually occurring between the ages of 30 and 50. High blood pressure is the most frequent cardiac manifestation, and this and other cardiac issues may lead to angina (chest pain), an abnormal heartbeat, heart attacks, and heart failure. Cerebrovascular disease often presents as strokes or brief episodes of blood loss to the brain (transient ischemic attacks).

Atypical Form

In the atypical form of Fabry disease, most of the classic symptoms do not manifest. The atypical form usually only causes problems of the heart or kidneys, later in life.

Additional considerations for carriers

XX individuals (who are typically assigned female at birth) are carriers and may be asymptomatic or may exhibit some of the symptoms of the classic disease. In most cases, symptoms are milder, with an onset later in life than for affected XY individuals. However, some carriers have severe symptoms.

How common is Fabry Disease?

The incidence of Fabry disease in the population is 1 in 40,000 in XY individuals. Because atypical forms may be unrecognized or diagnosed late in life, this incidence is likely an underestimate, and higher frequencies have been reported in both Taiwan and Italy.

How is Fabry Disease treated?

Pain may be treated with medications including diphenylhydantoin, carbamazepine, or gabapentin. Kidney disease can initially be treated with ACE inhibitors or angiotension receptor blockers to reduce protein in the urine. Late-stage renal involvement may require blood filtering (dialysis) or kidney transplantation.

There is evidence that enzyme-replacement therapy (ERT) may prevent some primary manifestations of Fabry disease, and it is typically recommended for all affected XY individuals (including children) and for some carriers. However, because ERT may not improve symptoms of kidney, cardiac, or cerebrovascular disease, other medications may be recommended to help manage kidney disease, heart disease, and stroke.

What is the prognosis for an individual with Fabry Disease?

The majority of affected individuals with Fabry disease live well into adulthood, with an average life expectancy of approximately 58 years. Kidney disease and cardiac disease are the main causes of mortality. For carriers, the prognosis is good and approaches a near-normal life span, though some individuals may be more severely affected.