Fabry disease is a rare genetic disease characterized by the accumulation of a type of fat called globotriaosylceramide (Gb3 or GL-3) inside cells. This build-up is due to the inability of the cells to break down Gb3 because of mutations in the GLA gene, which contains the information necessary for the production of an enzyme called alpha-galactosidase.
Fabry disease primarily has two recognized forms — type 1 (classical form) is the most severe and is associated with very little or no alpha-galactosidase activity, while type 2 (late-onset form) is milder with some residual enzyme activity.
Causes of type 2 Fabry disease
Similar to type 1 Fabry disease, the type 2 form is caused by mutations in the GLA gene. However, in type 2 patients, alpha-galactosidase enzyme activity is usually greater than 1%.
Several rare pathogenic (disease-causing) mutations in GLA are thought to be associated with type 2 Fabry disease. These mutations have been found to slightly alter the stability and function of the alpha-galactosidase enzyme, decreasing its activity.
One study, for example, has shown that individuals carrying the so-called p.N215S mutation are likely to develop type 2 Fabry with severe heart complications and, to a lesser extent, kidney problems.
Symptoms of type 2 disease
Unlike the classical type 1 form, type 2 Fabry disease patients do not show any symptoms during childhood or adolescence. Rather, they usually develop heart and kidney problems between the ages of 30 and 70.
Pathological changes in heart tissue in type 2 Fabry disease are only seen in adulthood (age 30 or older), but research has shown that Gb3 accumulation in heart tissue actually begins much earlier, before the formation of inclusion bodies — the presence of which is regarded as a confirmation of a Fabry disease diagnosis.
About 2% to 3% of type 2 Fabry patients age 40 or older have left ventricular hypertrophy (LVH). In LVH, the walls of the heart’s left ventricle become enlarged and thickened, which can lead to heart failure. LVH is more common in patients over age 40, with 32% of women and 67% of men with the disease being affected.
Chronic kidney disease (CKD) is seen in type 2 Fabry patients, although the risk is lower compared to type 1 disease. The build-up of Gb3 in kidney cells can lead to progressive kidney damage and, potentially, kidney failure.
Although cerebrovascular disease and stroke are more common in type 1 Fabry disease, research has shown an evident increase in white matter hyper-intensities (injury to the nerve cell fibers in the brain) and blood vessel obstructions in several brain areas in type 2 patients, changes that are not seen in healthy individuals.
A case study has reported that the presence of cramp-fasciculation syndrome (CFS) could be a symptom of type 2 Fabry disease associated with a so-called A143T mutation (here, a single letter change exists in the DNA code, from A to T at position 143). In CFS, persistent muscle twitching (fasciculation) and cramping leading to pain and discomfort are observed.
However, recent studies consider the A143T mutation to be a neutral variant and not necessarily disease-causing, as evidenced by normal Gb3 levels in these people.
Newborn screening can help identify GLA mutations associated with type 2 Fabry disease. Although these patients typically do not show any symptoms until adulthood, enzyme replacement therapy (ERT) can prove to be quite effective if initiated well before heart and kidney problems start to appear.
Last updated: Oct. 22, 2019
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