Fabry Disease – Symptoms and Treatment

Definition of the Disease. Causes of the Illness

Fabry disease (Anderson-Fabry disease) is a rare genetic disorder associated with the accumulation of a fatty substance in the body known as globotriaosylceramide (Gb-3, GL-3, ceramidetrihexoside). The disease is characterized by the development of skin lesions, pain in the extremities, poor vision, kidney failure, and heart disease.

Cutaneous manifestations of Fabry disease

The cause of Fabry disease is a mutation in the GLA gene, located on the short arm of the X chromosome (Xq22). This mutation leads to a decrease in the enzyme alpha-galactosidase A, which is responsible for breaking down globotriaosylceramide.
Gb-3 belongs to the class of sphingolipids – fats found in the cell membrane that protect the cell surface. Normally, they are broken down and removed from cells by the enzyme alpha-galactosidase A, but in the deficiency of this enzyme, Gb-3 accumulates in cells, begins to affect their normal function, and causes progressive damage to the body, accompanied by various clinical symptoms. The disease is classified as a sphingolipidosis, and sphingolipidoses belong to the group of lysosomal storage diseases, which are rare inherited metabolic disorders.
The prevalence of Fabry disease ranges from 1 in 40,000 to 1 in 120,000 newborns. The difference in data is due to difficulties in diagnosis and varying frequencies in populations.
The disease is named after the dermatologist John Fabry (J. Fabri), who first described a case of nodular purpura and subsequent albuminuria in a thirteen-year-old boy in 1898.

Symptoms of Fabry Disease

Main Diagnostic Criteria:

  • Burning pain in the distal parts of the limbs (feet and hands)
  • Characteristic skin manifestations
  • Cataracts
  • Keratopathy
  • Accumulation of trihexosylceramide in various tissues
  • Decreased activity of the enzyme alpha-galactosidase A in blood plasma, leukocytes, tear fluid, and fibroblast culture.

Symptoms of Fabry Disease

The initial signs of the disease, such as constant neuropathic pain, acute episodes of acroparesthesia (tingling and numbness sensations in the feet and hands), intolerance to high and low temperatures, and a feeling of fatigue, manifest in early school age. Affected males are characterized by a specific appearance: prominent supraorbital ridges and frontal bossing, prognathism (protrusion of the upper jaw), swollen lips, and a depressed nasal bridge.

Detailed Description of Clinical Symptoms
Excruciating episodes of acroparesthesia are typical for this disease. The patient experiences burning, tingling, and discomfort in the feet and hands, which occur with slight painful irritation. The severity of these episodes increases significantly over the years, they occur more frequently and become longer-lasting. Sometimes these pain episodes last for several days, accompanied by low-grade fever, signs of inflammation according to blood tests. Anderson-Fabry disease is characterized by the presence of painful crises – periodic intense exacerbation of painful symptoms spreading to the proximal parts of the limbs and trunk. Stressful conditions, overheating, chilling, changes in atmospheric pressure, physical exertion, and fatigue can exacerbate the condition.

Angiokeratoma is a typical vascular lesion in Fabry disease. It consists of cherry-red spots, slightly raised above the skin surface, painless. It consists of a conglomerate of several dilated vessels covered with superficial layers of skin. Located on the fingers of the upper and lower extremities, around the lips, in the genital area, anus, around the navel, and on the knees. It does not change color when pressed. Over the years, their number and size increase. Angiokeratomas usually manifest at an early age and progress over time.

Possible development of angiectasias (dilation of the lumen of blood vessels) on the mucous membranes of the oral cavity and eyes.

Ophthalmological symptoms include an increase in the diameter and tortuosity of retinal and conjunctival vessels, corneal opacity. Upon examination of patients using a slit lamp, light vortex-like deposits of the substrate in the cornea may sometimes be visualized, leading to funnel-shaped keratopathy (a corneal pathology that causes a decrease in its transparency and visual impairment). In the early stages of the disease, visual acuity remains unchanged, but over time, significant corneal opacity develops, which can lead to blindness. Damage to the optic nerve is rare but carries serious consequences.

Patients with Anderson-Fabry disease experience disturbances in sweating, such as hypohidrosis (decreased sweating) and sometimes anhidrosis (absence of sweating). This can lead to intolerance to high temperatures and overheating of the body.

Many patients, especially males, complain of poor tolerance to physical exertion and fatigue, which is associated with rapid overheating and intensification of paresthesias.

With age, the pathological process involves the cardiovascular system. Accumulation of sphingolipids in cardiac muscle cells and endothelium (inner layer) of blood vessels disrupts their functions and leads to fibrosis (proliferation of connective tissue). This manifests as shortness of breath, chest pain, arrhythmias, tachycardia, left ventricular hypertrophy detected by ultrasound, MRI, and ECG. Involvement of the cardiovascular system is the most unfavorable development of the disease.


Renal involvement is detected in all hemizygotes (males with a single mutant X chromosome). Chronic kidney disease progresses, which in the early stages has a latent course, without increased blood pressure, with normal or slightly elevated serum creatinine levels, and slight proteinuria (protein in the urine). Over time, renal failure reaches the terminal stage, severe uremia (severe self-poisoning of the body due to kidney failure), and arterial hypertension develop.

One of the most evident manifestations of the disease is neurological disorders. Patients complain of episodes of dizziness, headaches, and loss of consciousness. Due to the accumulation of sphingolipids in lysosomes of nerve cells and endothelium of blood vessels, ischemic conditions of the brain occur, resulting in transient ischemic attacks, ischemic, and hemorrhagic strokes in patients. Often, ischemic stroke at a young age is the only manifestation of the disease, especially in heterozygous women (having one normal and one mutant chromosome) and patients with an atypical type of disease. As a result of ischemic changes in the brain, patients become forgetful, scattered, untidy, and suffer from cognitive impairment.

Patients may complain of noise, ringing in the ears, sharp decrease in hearing acuity, leading to deafness. Neurosensory hearing loss is observed.

Gastrointestinal tract involvement manifests as abdominal pain, dyspepsia (difficult and painful digestion), diarrhea, flatulence, and constipation. In most patients, episodes of diarrhea are followed by constipation, and hemorrhoids develop. Sometimes gastrointestinal bleeding occurs.

Some patients experience mild iron-deficiency anemia that does not require correction. In males, there may be delayed physical and sexual development.

Often, patients with Anderson-Fabry disease are diagnosed with “rheumatic fever,” which is associated with episodes of low-grade fever and damage to the skeletal system. Bone disorders manifest as involvement of the pathological process in the distal interphalangeal joints, decreased mineral density of the vertebrae, and aseptic necrosis of the femoral and tibial bone heads.

In severe cases of the disease, with excruciating paresthesias, the patient’s emotional well-being is disturbed, leading to depressive and anxious states. In some cases, with intense painful manifestations of the disease, patients may have a tendency to suicide.

Pathogenesis of Fabry Disease

Fabry Disease is inherited in an X-linked recessive manner with complete penetrance (where the mutant gene shows its effect in each individual) and varying expressivity in males (hemizygotes). Some authors suggest an X-linked dominant type with incomplete penetrance (the gene is not expressed in all individuals). The mode of inheritance is currently a subject of discussion among experts.

The mutant gene on the X chromosome

In hemizygous males, the disease manifests with more pronounced symptoms, as in homozygous females (having two mutant X chromosomes). Heterozygous females (with one mutant X chromosome) often exhibit an atypical form of the disease, or they may remain healthy.

As already noted, the disease is caused by a mutation in the GLA gene located on the short arm of the X chromosome (Xq22). This gene encodes the synthesis of the enzyme alpha-galactosidase A, responsible for the breakdown of the sphingolipid globotriaosylceramide (Gb-3). Gb-3 carries a terminal galactose residue in its structure, which requires the enzyme alpha-galactosidase A for cleavage. A defect in the gene encoding this enzyme disrupts the breakdown process, leading to the deposition of glycosphingolipids with a terminal α-galactosyl residue in cells.

Normal breakdown process of Gb-3 and pathology

Sphingolipids are lipids derived from aliphatic amino alcohols. When their breakdown process is disrupted, there is an accumulation of ceramidetrihexoside in the lysosomes of cells. Excess substrate in the cells significantly impairs their viability, leading to changes in functions and clinical manifestations of the disease, disrupting nerve transmission and cell communication.

Accumulating in the vascular wall, kidneys, and myocardium, sphingolipids initiate fibrogenesis processes (formation of scar tissue), resulting in organ failure. Accumulation of substrate in the endothelial tissue of blood vessels leads to their narrowing, microcirculation disorders, and tissue hypoxia. This is the main mechanism for the development of ischemic disorders.

Accumulation of sphingolipids in nerve cells leads to structural changes: an increase in the number of calcium channels, the formation of pathological nociceptive connections, increased excitability of pain pathways, and the development of typical symptoms.

The development of hypohidrosis, as well as anhidrosis, is associated with the deposition of sphingolipids in sweat gland cells, impaired innervation, and reduced blood supply to the skin.

Accumulation of trihexosylceramide in the myocardium leads to the development of progressive hypertrophic cardiomyopathy, and in the presence of narrowing of the coronary vessels, this leads to ischemic cardiac symptoms, acute coronary syndrome, and the development of heart failure.

Hypertrophic Cardiomyopathy

It is presumed that the exacerbation of pain during physical exertion is associated with spasm of narrowed vessels, which leads to impaired nerve fiber trophism.

Deposition of substrate in the cornea leads to its opacity, and vascular involvement may contribute to worsening vision, up to blindness.

Classification and Stages of Fabry Disease

Two main forms of Fabry Disease are distinguished:

  • Classic
  • Atypical

The classic form is characterized by early onset of the disease (in the first decade of life) and the presence of characteristic symptoms and complications.

In the atypical form, there is isolated involvement of the brain (early strokes), heart, and kidneys. In this case, the disease manifests later in life and poses greater diagnostic challenges.

Some English-speaking authors also distinguish a female form of the disease. It has milder manifestations, typically starting 5-10 years later than the classic “male” form.

Complications of Fabry Disease:

Nervous System:

  • Ischemic strokes at a young age, often a cause of death.

Cardiovascular System:

  • Ischemic heart attacks
  • Cardiomyopathies
  • Arrhythmias
  • Heart failure leading to death.


  • Terminal (life-threatening) stage of kidney failure requiring kidney transplantation.

Other Systems:

  • Vision and hearing impairment, up to deafness.
  • Bone fractures
  • Overheating of the body.

Death most often occurs from uremia or ischemic brain and heart damage in the fourth decade of life.

Diagnosis of Fabry Disease

Early diagnosis is crucial for the proper and timely treatment of affected organs and for preventing complications.

A vital diagnostic method for Fabry Disease is assessing the patient’s family history. This may reveal relatives with similar symptoms who are unaware of their condition. Since the gene responsible for Anderson-Fabry disease can be passed down through many generations, both close and distant relatives of the patient may also have the disease. To determine the risk of inheriting the disease, it is necessary to gather information about the health of all known family members.

A preliminary diagnosis is made based on the results of patient interviews, collecting complaints, and assessing the family history. Methods for verifying the diagnosis include substrate and enzyme detection techniques, as well as DNA diagnostics.

  • Measurement of alpha-galactosidase A activity: In Fabry Disease, the activity of this enzyme is always below normal in males, while in females, this indicator may be within the normal range or slightly reduced. Materials for conducting the study may include leukocytes, plasma, tear fluid, and fibroblast culture.
  • The most accurate diagnostic method is DNA sequencing of the GLA gene. To date, more than five hundred mutations in this gene leading to Fabry Disease have been described. The use of this technique is limited by its cost. DNA diagnostics is advisable for use in women because determining alpha-galactosidase A activity may not always yield reliable results, and for relatives of the patient, as they may be carriers of the mutant gene or have an atypical form of the disease. This analysis can be conducted at the Center for Molecular Genetics in Moscow.
  • Quantitative determination of globotriaosylceramide: This method is used to monitor the condition of patients, assess the effectiveness of treatment, and determine the form of the disease (typical or atypical). Materials for research may include plasma or dried blood spots.
  • In some cases, a kidney biopsy is performed to detect cells containing lysosomes with characteristic substrate.

Fabry Disease can be very difficult to distinguish from more common conditions, and patients may remain without a correct diagnosis for many years. Differential diagnosis of Fabry Disease is conducted with hereditary hemorrhagic telangiectasia, rheumatic fever, Farber Disease, Schindler Disease, and other inherited storage diseases.

Treatment of Fabry Disease

Treatment of Fabry Disease involves enzyme replacement therapy to replace the deficient enzyme. This therapy is administered via intravenous infusion and is typically used alongside various methods to treat specific symptoms.

In Russia, two medications are currently used for enzyme replacement therapy: “Fabrazyme” by Genzyme and “Replagal” by Shire. These medications are very expensive, and treatment for patients is funded by the federal budget since the disease is classified as rare. There is legislation for expedited drug approval procedures for treating such diseases.

Enzyme replacement therapy is recommended for men immediately after diagnosis. To alleviate pain, medications from the groups of anticonvulsants, antidepressants, analgesics, nonsteroidal anti-inflammatory drugs, and narcotic analgesics are used. Patients are also recommended to use antihypertensive drugs.

In cases of terminal kidney failure, kidney transplantation is performed. It is not recommended for donors to be relatives of the patient. Hearing aids are recommended for correcting hearing loss. Physical activity for Fabry Disease patients should be limited due to the possibility of exacerbating symptoms and overheating.

Situations where enzyme replacement therapy is not advisable include pregnancy and lactation, the presence of another life-threatening condition where the prognosis with replacement therapy would not improve, and the presence of serious complications (ischemic stroke, critically ill patients).

Prognosis and Prevention:

With proper treatment and timely initiation of enzyme replacement therapy, the prognosis for patients is favorable. Without treatment, death from cardiovascular, neurological, and renal complications occurs in the fourth decade of life.

Prevention of the disease involves prenatal or preimplantation diagnosis of the mutant gene using DNA diagnostics. Additionally, pregnancy termination may be considered based on medical indications. Sometimes screening of dried blood spots with determination of alpha-galactosidase A activity is performed, but this is limited by regional financial capabilities.

All patients with signs of Fabry Disease and potential gene carriers should be examined to promptly initiate enzyme replacement therapy, prevent clinical manifestations of the disease, and its complications. For this purpose, a program is in place to regulate not only the collection and shipment of material to the Center for Molecular Genetics but also to provide patients with enzyme replacement therapy medications.