Fabry disease: what are the symptoms of this rare genetic disease?

Fabry disease belongs to a group of very rare diseases. Its incidence is less than 5 patients per 10 000 inhabitants.

These diseases are referred to as 'orphan diseases'.

They have their drawbacks. Since only a very small percentage of the population suffers from them, there is no pressure on pharmaceutical companies to support research and development of drugs for these rare diseases.

This is also the case with Fabry disease. We know the cause of this disease, but so far only symptomatic or replacement therapy is available.

Fabry disease is linked to the X chromosome. Women have two X chromosomes in their genome, men one X and one Y.

In this congenital disease, there is a large multi-organ damage.

They are caused by a metabolic defect in the breakdown of glycosphingolipids, which are stored in increased amounts in cell lysosomes (organelles containing enzymes) everywhere in the body.

The organs of the cardiovascular system and the kidneys are most affected.

Glycosphingolipids are, in simple terms, compounds of lipids with a carbohydrate component. They are derivatives of ceramide.

These chemical compounds have various important functions in the body. One of these is, for example, a structural function in cell membranes, which are more stable and stronger thanks to glycosphingolipids.

They are found mainly in the brain as cerebrosides and gangliosides, but also in some other organs such as the liver, spleen, kidneys, blood vessels and others.

The incidence of Fabry disease is approximately 1 in 40,000 cases. However, this number may be an underestimate. It is a rare disease and its diagnosis is not sufficient. Sometimes it is diagnosed only after the death of the patient.

The disease affects all races and ethnic groups. Men are affected more severely than women. Men are also diagnosed earlier and men do not live with the disease as long as women.

The disease was first described in 1898. Two German dermatologists, William Anderson and Johannes Fabry, independently noticed skin changes on their patients. They called them angiokeratomas. Therefore, the disease is also called Fabry-Andersen disease in older literature.

Other eminent scientists and physicians have also dealt with the disease. For example, Brady in the 19th century explained the cause of increased glycosphingolipid deposition on the basis of a defect in the enzyme alpha-galactosidase. Kornreich and his colleagues deciphered the genetic code of this enzyme, which allowed its laboratory preparation.

A genetic disease associated with the sex chromosome X means that a gene on the long arm of the sex chromosome X has been mutated.

This sex chromosome encodes, among other things, proteins for the production of a lysosomal enzyme called alpha-galactosidase.

In men, the disease is more severe and they tend to be affected by the full form. This is because they have only one X chromosome and it is affected by a mutation. They pass on this mutated X chromosome to the next generation, to all their daughters.

The healthy Y chromosome is passed on to the son. Sons never inherit the disease from their father.

Daughters, on the other hand, will inherit their father's mutated X chromosome and their mother's healthy X chromosome.

A woman with two X chromosomes can also be a carrier if her offspring inherit an X chromosome affected by the mutation. Statistically, one half of the offspring will get the healthy gene and the other half the mutated gene. In real life, it depends on chance.

There are about 200 known mutations of this gene that lead to Fabry disease.

When alpha-galactosidase is deficient, glycosphingolipid accumulates in lysosomes (hence the name "lysosomal disease"). Its excess damages the structure and function of the body's organs.

In addition to lysosomal dysfunction, oxidative stress and disturbances in cellular calcium and potassium channels also contribute to the damage, causing a dysregulation between nutrient uptake and output.

As a result, the energy metabolism of the cell is disturbed, causing its death.

Damage to blood vessels causes impaired nutrient and oxygen supply to tissues. Tissues become fibrotic. This means that functional organs become worthless, hardened, fibrous masses.

The symptoms of Fabry disease depend on the variant and on the residual function of the enzyme alpha-galactosidase. The clinical picture is therefore highly variable. Not every patient has the same course of the disease.

Sometimes only some of the symptoms may be present. Examples are women with later onset and milder forms of the disease.

There are several forms of Fabry disease.

The classic form with a fully developed clinical picture most often affects men. Atypical variants are subtypes in which the disease may predominantly affect only one organ system, e.g. the renal subtype or the cardiac variant.

The classical form of Fabry disease

This form develops when the activity of the enzyme alpha-galactosidase is less than 1% of normal.

Neurological symptoms

The first symptoms appear already in childhood. Children suffer from so-called acroparesthesia. This is an unpleasant tingling, burning, painful sensation on the edges of the hands and feet, especially in the fingers.

The cause of these strange sensations is damage to the thin peripheral nerve fibres. Patients may experience them every day and throughout the day. They worsen in environments with increased temperature, during fever, during exercise or in stressful or emotionally demanding situations.

Involvement of blood vessels increases the risk of clot formation with subsequent embolization to the brain. The patient suffers from frequent headaches and dizziness.

There is also an increased risk of sudden stroke when a clot occludes a blood vessel in the brain. This leads to insufficient blood supply, i.e. ischaemia. This is one of the life-threatening risks of Fabry disease.

Kidney damage

One of the most serious damages is loss of kidney function - nephropathy.

As early as the age of 20, laboratory signs of damage are present in the blood and urine. They start as microalbuminuria, i.e. the presence of the smallest protein molecules in the urine.

As the disorder progresses, the kidneys begin to "dump" larger particles of protein into the urine and proteinuria develops. With normal kidney function, protein is not present in the urine because the kidneys save it for the body's needs.

This disorder worsens with age. Glycosphingolipids gradually accumulate everywhere in the kidneys, in the kidney cells, renal tubules, blood vessels and smooth muscle.

These changes are unfortunately irreversible. Segmental glomerulosclerosis, i.e. the gradual loss and fibrosis of the most important renal unit, the glomerulus, occurs. Nitrogenous waste substances, especially urea, accumulate in the blood.

The final stage of the disease is renal failure. At this stage, sclerosis and atrophy of the renal tubules also occur.

Patients at this stage must be haemodialysed and prepared for the eventual need for a kidney transplant. This occurs between the ages of 40 and 50.

Damage to the airways

Accumulation of glycosphingolipids in the lungs and bronchi causes obstructive disease. It is manifested by shortness of breath at rest and during activity, wheezing when breathing, chronic cough and frequent bronchitis.

Cardiovascular impairment

Damage to blood vessels and the heart is the most common cause of death in patients with Fabry disease. Glycosphingolipids are deposited in the cells that make up the inner lining (endothelium) of the heart.

These changes in the heart cause impaired blood flow to the heart muscle itself. Patients experience pain behind the breastbone (angina) on exertion, become short of breath and are at risk of ischaemic heart damage with subsequent myocardial infarction and death.

Remodelling of the heart muscle leads to so-called hypertrophic cardiomyopathy, where the left ventricle in particular is thickened and enlarged. This thickened muscle has greater nutritional requirements and is therefore more prone to ischaemia.

Furthermore, this muscle fibroticises, thereby losing the ability of the heart to pump efficiently.

The heart valves are also affected. Damage to them causes mitral or tricuspid valve regurgitation or prolapse.

Arrhythmias or heart rhythm disturbances are a common symptom of Fabry disease in young and active people in their twenties. They pose a high risk of unexplained sudden death in a young person.

Up to a fifth of these patients have a pacemaker implanted during their lifetime.

Skin symptoms

The most striking symptoms of Fabry disease are the numerous skin growths called angiokeratomas. These are wart-like formations.

They are most commonly found in the area between the navel and knees, on the thighs, groin and buttocks. Some are also visible in the mouth.

Angiectasias are small, purplish-red dots that have formed by the enlargement of a tiny blood vessel in the skin whose vascular wall has weakened. Their number increases with age.

Patients with Fabry disease have difficulty sweating. This symptom is called hypohidrosis or anhidrosis. The cells of the sweat glands in the skin and the autonomic nervous system that controls secretion from these glands are damaged.

Because the patient cannot regulate his body temperature, he suffers from intolerance to heat or cold.

Gastrointestinal symptoms

Digestive disorders appear in patients at an early age. They are caused by increased deposition of glycosphingolipids in the autonomic ganglia of the intestine and the abdominal vessels.

Patients suffer from frequent diarrhoea and abdominal pain, which occur when there is increased intestinal activity, i.e. especially after meals. Other symptoms include bloating, nausea and vomiting. Patients therefore suffer from inappetence and lose weight significantly.

Ocular symptoms

Fabry disease significantly affects the eyes and vision of the individual. Typical is damage to the cornea of the eye called cornea verticillata.

It is characterized by spiral-shaped formations on the cornea that are visible when examined with a slit lamp by an ophthalmologist.

In addition, all patients are affected by corneal opacity.

Vascular damage to the eye, especially to the blood vessels that nourish the retina, can cause impaired visual acuity and even blindness.

Fabry's cataract is the name for a subcapsular cataract. The lens is clogged with granules from excess lipids.

Hearing symptoms

Tapping, whistling, humming, buzzing and other unpleasant sounds heard in the ears without any surrounding stimuli are called tinnitus. It is the first sign of hearing damage.

Damage to the inner ear and its blood vessels progresses to complete deafness. In addition to the organ of hearing, the inner ear also houses the organ of balance, which maintains the stability of the body.

When it is damaged, patients suffer from dizziness and gait disturbances. They are often unable to maintain their balance.

Other symptoms

The deposition of glycosphingolipids in the walls of lymphatic vessels and lymph nodes causes impaired lymphatic drainage. As a result, swellings occur, especially in the lower limbs. They may also occur elsewhere on the body, usually asymmetrically.

Priapism is the term for a painful erection that is present without sexual arousal or lasts more than 4 hours after sex.

A significant symptom that impairs the quality of life of almost all patients is impaired psychological well-being, depression, anxiety disorders, and even suicidal tendencies.

If patients have at least some α-galactosidase enzyme activity, the clinical picture of their disease may not be fully developed. Such forms are called atypical.

The disease predominantly affects one organ, e.g. heart, kidneys, eyes, etc. The first manifestations appear later than in the classical form, usually after the age of 40.

Fabry disease is often diagnosed in its later stages, when major organ systems, the heart and brain, are already irreversibly affected.

Making such a rare diagnosis is challenging, but should be kept in mind during diagnosis.

A thorough physical examination and patient history with a focus on family history are key. A cautionary finger is raised if the patient reports unexplained deaths of younger family members from ischemic events, heart attacks, kidney or respiratory problems, etc.

Examination should focus on these signs and symptoms:

• angiokeratomas on the skin
• Angiectasia
• dry hands, heat intolerance
• blurred, foggy vision, high dioptres
• heart rhythm disturbances
• enlargement of the heart on ECHO examination
• non-contractile or eroded valves
• elevated blood creatinine levels above normal
• elevated total protein, sodium, presence of glycosphingolipids on 24-hour urine collection
• magnetic resonance imaging of the brain
• angiography of cerebral vessels
• examination of the lungs and sputum (coughed sputum)
• gastrofibroscopy
• ENT examination and audiometry
• blood count and blood biochemistry
• urinary sediment examination
• psychological or psychiatric counselling

Organ biopsies

This involves taking a tissue sample which is then examined under a microscope, called a histological examination.

In Fabry disease, samples are mainly taken from the skin, kidneys, stomach, heart or lungs.

The amount of accumulated deposits of glycosphingolipids in the cells is determined.

Examination of enzyme activity

The activity of the enzyme alpha-galactosidase A, which is inactive in Fabry disease, is examined.

It is detected from plasma and blood cells.

The most modern enzymatic test is the fluorimetric method.

Genetics

Genetic testing is aimed at detecting mutations in the Xq 22 gene.

It is important that when an individual is first diagnosed, genetic testing is carried out on other family members. This will greatly speed up diagnosis and treatment.

It is also possible to search for the genetic mutation before the offspring is born. This is called prenatal diagnosis.

DNA is tested from chorionic villi. These are the parts of the placenta that float freely in the amniotic fluid and contain the baby's genetic information. Amniocentesis, the collection of amniotic fluid, is carried out at 14 weeks of pregnancy, and only in boys.

The classic type of Fabry disease begins to manifest itself in boys quite early in childhood. The average age of patients with the first difficulties is 3 to 10 years.

They usually begin with acroparesthesia of the hands and feet. They also develop decreased sweating, heat intolerance, frequent and severe fevers, skin growths and visual disturbances.

Kidney involvement tends to be severe. Kidney involvement begins as early as between 20 and 30 years of age.

Around the age of 40, patients develop heart problems and neurological problems.

At this age, patients are already on hemodialysis due to kidney failure.

The most common cause of death is myocardial infarction followed by heart failure and sudden ischaemic stroke.

Thanks to symptomatic treatment and modern diagnostic methods or genetic analyses, patients are now living to an older age.

The average survival time for men is 50-60 years. Affected women live to an older age of 60-70 years due to milder disability.