Fabry disease, a rare genetic disorder caused by mutations in the GLA gene, can be classified in two forms — classic and late-onset — depending on the amount of enzyme function patients have lost.
At issue are mutations in GLA, which provides cells with the instructions to make the alpha-galactosidase A enzyme known as Gal A.
This enzyme is responsible for breaking down a fatty substance called globotriaosylceramide, or Gb3, which instead accumulate in a patient’s organs. People with Fabry experience a progressive buildup in Gb3 that results in organ damage and a wide range of serious symptoms.
Classic Fabry, which is the less common form, typically manifests in childhood, while late-onset disease, as its name suggests, usually begins with symptoms in the 30s or 40s.
Classic Fabry disease
More than 965 mutations in the GLA gene have been reported to cause Fabry. Yet, distinct mutations affect Gal A production differently, meaning that patients will not all have the same levels of the enzyme.
When patients have mutations that result in little to no Gal A activity — characterized as less than 3% of normal activity — the body is unable to clear out most Gb3. This fatty molecule thus builds up in most tissues from a very young age, causing the most severe symptoms of the disease.
The first symptoms of classic Fabry typically appear in childhood or adolescence, and include a feeling of burning pain in the hands and feet called acroparesthesia. Other symptoms are a decreased ability to sweat, and the appearance of clusters of reddish or dark-blue spots on the skin, known as angiokeratomas.
Gastrointestinal problems, such as pain, cramping, and frequent bowel movements, are all common early symptoms of Fabry, as is a characteristic starburst pattern on the cornea, which is the clear part over the lens of the eye. Many children and teens with Fabry also experience frequent headaches and fatigue.
As patients age, the accumulation of Gb3 in blood vessels and capillaries can lead to more severe heart problems, such as an irregular heartbeat and heart muscle thickening. These problems can lead to heart failure, as well as progressive kidney disease and stroke.
Late-onset Fabry disease
Late-onset Fabry is threefold to 10 times more common than the classic form, and is associated with a greater level of residual Gal A activity (3% to 15% of normal) — meaning that patients are still able to break down some Gb3.
While the fatty molecule still builds up in tissues, this happens at a much slower rate and to a lesser extent, leading to milder symptoms that appear only later in life. Patients with late-onset Fabry generally have a normal childhood and adolescence, and start experiencing symptoms sometime between the ages of 30 and 70.
As in classic Fabry, people with the late-onset form also experience organ damage, mostly in the heart, kidney, and brain. But the percentage of patients who experience severe problems in these organs is much lower.
Fabry disease in males and females
Fabry disease is an X-linked disorder — meaning that the mutated gene is carried on the X chromosome — and is much more common among men than women.
Because males have only one X chromosome (inherited from the mother), those who inherit a mutated GLA gene will develop the disease. Whether a patient will develop classic or late-onset Fabry disease will depend on the specific mutation.
Females have two X chromosomes, but during development, each of their cells undergoes a process called X-chromosome inactivation, which randomly “turns off” one of the X chromosomes to avoid duplication of genetic information. This makes Fabry inheritance in females more complicated.
If a female inherits a GLA mutation, a healthy copy of the gene on her other X chromosome may compensate for the mutation and produce enough enzyme to prevent the disease from manifesting or to make symptoms milder. If cells inactivate the chromosome with the healthy gene copy, however, that patient will likely develop the disease.
Thus, the type of Fabry that manifests in female patients depends both on the specific GLA mutation and on how much the healthy gene copy can compensate for the lost Gal A activity.
Last updated: Dec. 3, 2021
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