Fabry disease is a rare genetic condition characterized by the accumulation of fatty molecules, mainly globotriaosylceramide (Gb3 or Gl-3), inside cells, causing damage mainly to the heart, kidneys, and central nervous system (the brain and spinal cord).
Fabry disease is caused by mutations in the GLA gene, which is located in the X chromosome (one of the two sex chromosomes, the other being the Y chromosome). Chromosomes are the structures that hold DNA in a densely packed form in the nucleus of cells.
The GLA gene provides the instructions to produce alpha-galactosidase A (Gal A), an enzyme that is active in lysosomes — the cell’s recycling center — and is responsible for breaking down fatty molecules, such as Gb3 and lyso-Gb3.
Mutations in GLA result in absent or markedly deficient Gal A enzyme activity, leading to the toxic accumulation of Gb3, lyso-Gb3, and other related molecules inside lysosomes. This toxic build-up causes tissue and organ damage. For this reason, Fabry disease is classified as a lysosomal storage disorder.
More than 950 Fabry disease-causing GLA mutations have been identified to date. Those resulting in the production of an enzyme that is completely abnormal or that has very low activity (less than 3% of normal) cause the classic, more severe type of Fabry disease, which usually develops in childhood or adolescence. Mutations generating an enzyme with some residual activity (3%–15% of normal) lead to the development of a later-onset, somewhat less-severe (atypical) form of the disease.
Fabry disease is inherited in a X-linked dominant manner, meaning that a person has to inherit one mutated version of the GLA gene in the X chromosome to develop the disease.
Since males have only one X chromosome (inherited from the mother), those who inherit the mutated gene will have more severe disease. 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.
Due to the presence of two X chromosomes in females, 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 means female Fabry patients typically show a mosaic pattern of cells producing a working Gal A enzyme, and cells with no to low levels of Gal A activity.
The type, severity, and timing of the symptoms in female patients vary greatly depending on the number of cells with the disease-causing GLA mutation in each tissue or organ. In rare cases, female patients may live their entire life without any signs of disease.
Men with Fabry disease will transmit the GLA mutation to all their daughters (who will typically develop the disease), but not to a son because boys receive a Y sex chromosome from their fathers, instead of an X chromosome.
Most female patients, who carry only one mutated GLA gene copy, will have a 50% chance of passing the mutated gene to each of their children, regardless of sex. In extremely rare cases of females with two defective copies of the GLA gene, all descendants will inherit one mutated copy and develop the condition.
Fabry disease is estimated to affect about one in every 40,000 to 60,000 men worldwide, but its frequency in females is less known. The condition is found in all populations and ethnic groups and its prevalence varies across different geographical regions.
The most common, late-onset form of Fabry, which has mild symptoms that usually begin in adulthood, is present in approximately one in 1,000 to 3,000 males and one in 6,000 to 40,000 females.
As for the classic form of Fabry, which begins in childhood and is more severe, it is estimated to affect one in 22,000 to 40,000 males. Its prevalence in females is unknown.
As more newborn screening studies are conducted, researchers are starting to realize that Fabry is underdiagnosed, and that it affects more people than previously estimated. Current studies estimate that about 0.04% of newborns (or one in every 3,000) will develop the condition.
Last updated: Nov. 12, 2021
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