Hereditary diseases: Fabry (or Anderson-Fabry) disease

By Cristiano Antonino On May 30, 2023

A serious hereditary disease caused by a mutation in the GLA gene, Fabry disease is characterised by the accumulation of sphingolipids in lysosomes

Microscopic vesicles filled with lytic enzymes to process organic substances, lysosomes are responsible for isolating enzymes with lytic activity from the rest of the cell, which could otherwise attack and destroy it.

Also called Anderson-Fabry disease, diffuse angiokeratoma and alpha-galactosidase A deficiency, Fabry disease usually manifests itself in childhood with pain and the appearance of reddish spots (especially on the thighs and groin), and then progresses to affect the heart, nervous system, kidneys and blood vessels.

The average lifespan of sufferers is 40 years but, thanks to the treatments available today, it is possible for sufferers to live longer.

The prognosis is all the better the earlier the treatment is instituted.

In most cases, this consists of the administration of the enzyme alpha-galactosidase but may sometimes require dialysis or a kidney transplant.

Of the lysosomal storage diseases, Fabry disease is the most common.

It is estimated to affect 1 in 80,000 people, but considering late-onset cases, the incidence is around 1/30,000.

What is Fabry disease?

Fabry disease is a rare and serious genetic disorder.

It occurs when the GLA gene (located on the X chromosome) undergoes a change that impairs its function.

The GLA gene produces the enzyme alpha-galactosidase A, which is essential for the lysis of globotriaosylceramide.

If this does not function as it should, molecules upstream of the process accumulate inside the lysosomes, damaging the cells.

The person manifests neurological, dermatological, ocular, gastrointestinal, cerebrovascular, renal and cardiac symptoms.

Fabry disease belongs to the group, comprising some fifty exponents, of lysosomal storage diseases.

In each of these diseases, lysosomes do not function properly for different reasons.

Underlying Fabry disease is a mutation in the GLA gene, located on the X sex chromosome

This gene is necessary for the production of the enzyme alpha-galactosidase A, which is needed to break down globotriaosylceramide into simpler molecules.

In patients suffering from Fabry disease, the production of alpha-galactosidase A is lower.

As a result, non-decomposed globotriaosylceramide molecules accumulate in the lysosomes and the cells suffer.

The cells most affected are those of the blood vessels, kidneys, heart and nervous system.

The disease is hereditary.

Specifically, it is a recessive hereditary disease linked to the X chromosome.

This means that, for the most severe symptoms to occur, all the X chromosomes of all cells must contain the mutated GLA gene.

Thus, if the mutation affects only one chromosome (in the case of two, i.e. in women), the person does not show severe symptoms but is a healthy carrier of the disease.

So-called ‘compensation’ occurs: the healthy X chromosome compensates for the mutated X chromosome.

If a healthy carrier has a child by a healthy man, the male child has a 50% chance of being born sick, since in male subjects (who have only one X chromosome) the compensation mechanism does not occur.

For a female to be born sick, she must be the daughter of a healthy carrier and a sick male. Hence, Fabry Disease is a predominantly male disease.

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The symptoms

Fabry Disease generally manifests itself in the first years of life, but the symptoms are mild and vague (which is why it is almost always diagnosed when symptoms worsen).

Typical symptoms of the disease are:

gastrointestinal pain, due to a malfunction of the blood vessels;
pain in the hands and feet (acroparesthesia), probably caused by damage to peripheral nerves: the fingers, soles of the feet and palms of the hands are painful;
dark spots on the skin (angiokeratomas): small, asymptomatic, dome-shaped, red-blue-black vascular formations that affect more than 80% of patients and are concentrated in the pelvic area;
chronic diarrhoea, which may occur up to 12 times in a day and is often accompanied by cramps in the lower abdomen, alternating with periods of constipation
postprandial nausea;
feeling of fullness and heaviness during meals;
renal problems, which usually begin in childhood with proteinuria (abnormal amounts of protein in the urine) and microalbuminuria (presence of albumin in the urine). If not treated promptly, these problems can lead to chronic renal failure which, at an advanced stage, can only be resolved with dialysis or a kidney transplant;
hearing problems, from tinnitus (high-frequency intermediate tinnitus) to deafness
dizziness;
corneal opacity (or cornea verticillata), intra-epithelial corneal deposits of yellowish-brown lipid particles that do not impair vision;
anhydrosis (inability to secrete sweat) or hypohidrosis (reduction in the amount of sweat produced);
cardiac problems, from cardiac and ventricular arrhythmias to left ventricular hypertrophy and restrictive cardiomyopathy and enlarged heart.

Fabry disease, especially if not detected in time, can cause serious consequences to internal organs

First of all, it can cause kidney damage, but also heart disease and predispose the individual to thrombosis, stroke and ischaemia.

As the disease progresses, it comes to affect the neurological, dermatological, gastrointestinal, ocular, cardiovascular and renal areas.

Diagnosis

Being a hereditary genetic disease, Fabry Disease cannot be diagnosed without an accurate family history: in fact, it is possible that several members within the family suffer from it.

Screening can be carried out simply by taking a blood sample, as prescribed by a doctor.

In this way, family members in whom the ‘defective’ gene is present but who have no symptoms will be constantly monitored, while those who have already developed symptoms can be treated immediately.

The actual diagnosis of Fabry disease is made by means of a blood test to check the activity levels of the enzyme alpha-galactosidase (alpha-GAL), which are very low in people suffering from the disease.

Another important test is the genetic test to check for the presence of the mutation on the GLA gene on the X chromosome.

Therapy

The therapy for Fabry disease is enzyme replacement therapy: the patient is given a copy of the enzyme alpha-galactosidase A, created in the laboratory.

In this way, the functions of the enzyme are vicariated by the exogenous enzyme.

To date, a cure from the disease is not possible; the GLA gene mutation is permanent, but with the right therapy, symptoms can be reduced and life expectancy extended.

The prognosis is now 58.2 years for men and 75.4 for women (compared to 74.7 and 80 for healthy individuals).

The most commonly used drugs are:

Fabrazyme, a solution administered by drip whose active ingredient is agalsidase beta;
Replagal, a solution for infusion containing the active substance agalsidase alpha;
Galafold, a capsule medicine reserved for patients over the age of 16.

The doctor may then prescribe, depending on the symptoms experienced, painkillers, medicines against gastrointestinal disorders, blood thinners, medicines against hypertension, medicines to regulate the heartbeat and – in the most severe cases – dialysis.

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