Fabry disease, a rare genetic condition caused by GLA gene mutations, has two recognized forms: classic, which typically manifests in childhood or adolescence, and late-onset, generally beginning after age 30.
Classic Fabry is more severe, but the disease in both forms affects the heart, nervous system, and kidneys, often leading to life-threatening symptoms.
The disease is caused by mutations in the GLA gene, which provides the instructions for making the alpha-galactosidase A (Gal A) enzyme, responsible for breaking down a fatty substance called globotriaosylceramide (Gb3). The absence or markedly deficient activity of this enzyme in patients results in the progressive buildup of a Gb3, leading to organ damage and a wide range of serious symptoms.
Very little or no Gal A activity is associated with classic Fabry disease. Meanwhile, late-onset (or non-classic) Fabry is tied to some residual enzyme activity, which leads to the later symptoms and a milder disease course.
Causes of classic Fabry disease
More than 965 mutations in the GLA gene have been reported to cause Fabry. When such mutations result in little to no Gal A activity — characterized as less than 3% of normal activity — Gb3 builds up in most tissues. Specifically, Gb3 accumulates in their small blood vessels, beginning from a very young age, and leading to the classic subtype of the disease.
Individuals who preserve a higher level of enzyme activity — 3%–15% of normal — are able to break down some Gb3. This fatty molecule will still build up in tissues, but to a lesser extent and at a slower pace, resulting in milder symptoms that manifest only later in life.
Classic Fabry disease in males and females
Fabry disease is an X-linked disorder, meaning that the GLA gene is located on the X chromosome. Since males have only one X chromosome (inherited from the mother), those who inherit the mutated gene will have the disease.
It is estimated that 1 in 22,000–40,000 males will develop classic Fabry.
In females — who have two X chromosomes, one from the mother and one from the father — the typical presence of a healthy gene copy can compensate to a certain extent for the mutated copy. Thus, even if a female has a mutation associated with classic Fabry, the healthy gene copy can make enough enzyme to prevent the disease from manifesting or to make symptoms milder.
The frequency of classic disease in females is currently unknown.
Symptoms of classic Fabry disease
The first symptoms of classic Fabry typically appear in childhood or adolescence, and they worsen over time. The disease can affect many organs and cause a wide range of problems.
One of the early signs of classic Fabry is a sensation of severe burning pain in the hands and feet, called acroparesthesia. It typically appears during stressful conditions and may last hours. Other symptoms that usually appear early on are a decreased ability to sweat, known as anhidrosis, and the appearance of clusters of reddish or dark-blue spots on the skin, called angiokeratomas.
Patients can have gastrointestinal problems, such as diarrhea and constipation, early in their disease course, as well as frequent headaches, fatigue, and dizziness. Delayed puberty may occur in some patients. Individuals also may experience hearing loss. Males are more likely to develop depression.
With the progressive accumulation of Gb3, organs like the kidney, heart, and brain also become progressively damaged, leading to more severe problems.
Kidney disease may progress to kidney failure, particularly in males, who may require dialysis or a transplant, usually between the ages of 35 and 45. In females, kidney involvement is more variable, progressing to kidney failure in about 10%–15% of patients.
Typically around their 20s, males with classic Fabry begin experiencing heart symptoms such as irregular heartbeat (arrhythmia) and a malfunction in the mitral valve, leading to a backflow of blood in the left side of the heart. To ensure that enough blood is leaving the heart, muscles surrounding the heart chamber contract harder and become thicker than normal. This creates strain on the heart and may eventually lead to heart failure. These heart conditions also may occur in females, but normally start a decade later.
The accumulation of Gb3 in the brain’s small blood vessels may sometimes affect blood supply to that organ, resulting in a stroke. About 7% of males and 4% of females with classic Fabry experience a stroke, typically after their 40s.
Patients also can experience respiratory problems due to tissue scarring and remodeling in their lungs, and males sometimes experience swelling in their feet and legs due to excess lymph accumulation.
Last updated: Nov. 4, 2021
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