Fabry disease, also called Anderson-Fabry disease, is a rare hereditary disease, transmitted recessively by the X chromosome, the female sex chromosome. Patients with Fabry disease have health problems because they have a deficiency of an enzyme called alpha-galactosidase A.
All humans have 2 sex chromosomes. Men have a Y chromosome and a sex chromosome X. Women have two sex chromosomes X and no Y chromosomes.
Each of the sex chromosomes that we have was transmitted by one of the parents. For example, when a couple has a male child, it means that the boy received the Y chromosome from his father and the X chromosome from the mother, thus forming the XY pair. When the couple has a girl, she receives an X chromosome from the father and an X chromosome from the mother, forming the pair XX. Therefore, since the mother is only able to pass the X chromosome to her children, whoever "decides" the child's sex is always the chromosome of paternal origin. If the father passes a Y, it will be a boy; if he passes the X, it will be a girl.
Fabry disease is a disease transmitted by a defective X chromosome.
When we say that Fabry is a disease recessively transmitted by the X chromosome, this means that for the disease to manifest in the women they need to receive the 2 X chromosomes (one from the father and the other from the mother) with the defect. If one X chromosome is healthy and the other sick, the woman does not develop the disease because the healthy chromosome protects her from that defect. Because men only have one X chromosome, they can not have another X chromosome to protect it. Therefore, a defective X chromosome is sufficient for it to develop Fabry disease.
From what has been explained so far, it is easy to understand why Fabry disease is a pathology that affects men much more than women. It is also easy to understand why the disease in males is always inherited from the mother, since male males are required to receive the father's Y chromosome and X chromosome from the mother.
Following this reasoning, we can say that men who have Fabry disease are not able to pass it on to their male children, since they receive only their Y chromosome. However, the female daughters of parents with Fabry will receive a defective X chromosome. However, as already explained, these daughters will only have Fabry if they also receive a defective X chromosome from the mother.
Summing up:
Fabry disease practically only occurs in men.
For a woman to have Fabry, she needs both parents to have the defective X chromosome*.
Women tend to be asymptomatic carriers of the defective X chromosome because their otherwise healthy X chromosome protects them from disease.
They are asymptomatic carriers of the defective X chromosome that transmit the defect to their children.
* This concept has been changing in recent years, as there are recognized cases of women with only one defective X chromosome that have distinct degrees of clinical manifestations of Fabry disease.
As already said at the beginning of the text, Fabry disease is caused by a deficiency of an enzyme called alpha-galactosidase A (alpha-gal A). This is an enzyme present within our cells and responsible for the elimination of a fatty substance called globotriaosylceramide (GB3 or GL-3). I know that these names sound like bad words, and that disturbs the understanding of the subject a little, but unfortunately that's the way they are called.
In the absence of alpha-gal A, GB3 accumulates inside cells, depositing in various tissues, mainly in the walls of blood vessels. Hence, Fabry disease is part of a group of pathologies called reservoir diseases.
All signs and symptoms of Fabry disease are derived from this buildup of GB3, which can clog vessel blood vessels, causing ischemia and infarctions of organs and tissues.
The symptoms of Fabry's disease usually follow a certain order of appearance. Early signs appear in childhood or early adolescence and include:
Pain in the limbs, mainly hands and feet, caused by involvement of the nerves of the peripheral nervous system. Usually this is the first symptom and can be triggered by stress, cold, heat or strenuous physical activities.
Skin lesions: Teleangiectasias are small dilated skin vessels, also called vascular spiders by their shape. They are commonly seen in people with varicose veins in the legs. Angiokeratomas are purplish punctate elevations.
In Fabry disease, the two lesions usually appear together mainly in the thighs, hip and around the navel.
Another common problem in Fabry is the involvement of the sweat glands, responsible for the production of sweat. Patients may have low rate of sweating (hypohidrosis), high body temperature, intense fatigue and heat intolerance.
Deposits of GB3 in vessels of the cornea of the eye, causing the so-called cornea verticilata can also be detected with special eye exams (ophthalmoscopy of slit lamp).
Gastrointestinal symptoms such as pain after feeding, nausea and diarrhea are also common.
In adulthood the patient begins to suffer the consequences of the obstruction of vessels in noble organs like kidneys, brain and heart.
1) Kidneys
50% of patients with Fabry disease have renal impairment. The first signs are increased urine output due to inability of the kidney to retain water. Then proteinuria and finally chronic renal failure. Most patients end up needing hemodialysis.
2) Heart
Cardiac involvement usually occurs in the form of heart failure, cardiac arrhythmias, left ventricular hypertrophy and myocardial ischemia.
3) Brain
The involvement of the central nervous system can occur through transient ischemic attacks or stroke, dizziness, vertigo and headaches.
Fabry disease in women
Most women carry only one defective X chromosome, and therefore have few or no symptoms of Fabry disease. However, by factors not yet well known, there is a small group that develops the disease just like men.
Because it is a rare and little known disease, even among physicians, patients often need to wait years between the first symptoms and the definitive diagnosis. When there is family history, the diagnosis comes out more easily, since the family itself already suggests the hypothesis of the disease to the doctor.
The triad of renal changes + angiokeratomas + limb pain in children or young males should always raise the suspicion of Fabry disease.
Diagnosis can be confirmed by dosing the alpha-galactosidase A enzyme. Most patients have undetectable or very low levels.
Skin or kidney biopsy may provide the diagnosis in those atypical cases where the physician does not initially think of Fabry disease as a differential diagnosis.
Women with the disease gene may be asymptomatic and have normal alpha-gal levels. In these cases only genetic tests can confirm if it has the disease gene, being able to be transmitted to their children. Genetic analysis is still done in very few laboratories.
Fabry disease has no cure. However, there is already a synthetic form of the alpha-gal A enzyme for administration. The two currently marketed brands are Replagal and Fabrazyme.
Currently the average life expectancy is around 50 years. The drugs are very recent and there is still no time to prove a decrease in mortality despite the evidence that there is a reduction in GB3 deposits and a delayed loss of renal function.
The sooner the drug is started, the better the results. The treatment is for life.
