WHAT IS FABRY

Fabry disease is a rare, genetic condition which is estimated to affect around 1 in 100,000 people.
In Fabry, an enzyme called α-galactosidase A (α-Gal A) is missing or there is a reduced amount. This means that the body cannot break down a certain type of fat called globotriaosylceramide (GL-3). GL-3 continues to build-up in body cells causing damage to tissues and organs.
Gradually, this leads to a range of physical symptoms and complications, which vary from one person to another.
Disease progression may be influenced by the sex of the individual (male or female) and how the disease presents, called its phenotype, which is classified as either non-classical (mild form) or classical (severe form).

Symptoms in Fabry

Day to day symptoms in Fabry are known to vary from one person to another.

BRAIN AND NERVES

  • Burning in the hands and feet
  • Intolerance to heat/cold
  • Mini stroke (TIA)/Stroke
  • Pain
  • Vertigo/feeling dizzy

HEART

  • Enlarged heart
  • Heart attack
  • Heart failure
  • Irregular heartbeat

KIDNEYS

  • Decreased kidney function
  • Kidney failure
  • Protein in urine

EYES AND EARS

  • Cloudy vision (cataracts)
  • Hearing loss (in children)
  • Ringing in ears

SKIN

  • Small dark red/purple spots located between the belly button and the knees
  • Sweating less than normal

OTHER

  • Cough/wheezing
  • Shortness of breath
  • Tiredness that is not relieved by rest or sleep

GI SYMPTOMS

Approximately 52–66% of Fabry patients report GI symptoms.
GI symptoms in Fabry vary from one person to another but often include:

  • Nausea
  • Diarrhoea
  • Abdominal cramps and pain
  • Bloating and frequent gas
  • Constipation
  • Feeling full before finishing a meal
  • Vomiting
  • Food intolerance

PSYCHOLOGICAL

Physical symptoms vary over time and do not always respond to symptomatic treatment which can, in turn, lead to psychological problems, such as depression and anxiety.

Inheritance

As Fabry disease is an X-linked disorder it can be passed to children by either parent

Mother

A mother with Fabry has a 50% chance of passing her X mutation to any of her children

Father

A father with Fabry passes his X mutation to all of his daughters. His son’s do not inherit Fabry because they inherit his Y chromosome

A mutation is a permanent alteration in the DNA sequence
that makes up a gene

  • Fabry is caused by a mutation in the α-galactosidase A gene (GLA) on the X chromosome
  • More than 1000 different mutations which cause Fabry disease have been identified
  • The mutation type may indicate what symptoms an individual will have, when they will appear and how bad they will be or will become

Testing and Diagnosis

An early diagnosis of Fabry disease is useful for many reasons, including starting symptom management, reducing the risk of further problems happening as well as early identification of other family members who may be affected. Initially, a combination of the signs and symptoms may lead your doctor to think you may have Fabry disease. Your doctor may then refer you to a specialist centre for a diagnosis of Fabry disease to be confirmed and for any treatment to be initiated. Anyone who is thought to have Fabry disease can have the diagnosis confirmed through laboratory testing. This test, called an enzyme assay, measures the amount of alpha-GAL enzyme activity in the blood. In males this can be done by taking a blood sample which is then tested to check the level of the a-Gal A enzyme. If the level of the enzyme is very low a diagnosis of Fabry disease can be made. This test can also be used to confirm the diagnosis of Fabry disease in females, although a laboratory genetic test in which DNA is analysed is a more effective test for confirming the diagnosis in women especially where there is a family history of Fabry disease.

Prenatal diagnosis is possible by measuring the a-Gal A activity in tissue or fluid taken from around the foetus. This test may be offered to expectant mothers who have Fabry disease. Specialist support and advice are available for such testing. An examination of your family history may indicate the presence of Fabry disease, particularly if a male relative suffered from kidney failure, heart disease or stroke early in life. To help identify whether there is the possibility of you or any of your relatives having Fabry disease, you can complete a medical family tree.

Misdiagnosis is common in Fabry disease due to its rarity. Fabry disease has been mistaken for;

  • Meniere’s disease

  • Crohn’s disease

  • Multiple sclerosis

  • Rheumatic fever

  • Arthritis

  • Raynaud syndrome

  • Irritable bowel syndrome

  • Erythromelalgia

Treatment

There is no cure for Fabry disease but current treatments may prevent organ damage and greatly improve the quality of life of patients.

ORAL CHAPERONE THERAPY

Chaperones are small molecules that assist enzymes in becoming functional by helping them take the correct shape and stay stable. Chaperone therapy is only suitable for people with amenable mutations of the α-GaL A enzyme. Treatment has shown meaningful reduction in diarrhoea in patients with Fabry disease and amenable mutations.

INTRAVENOUS ENZYME REPLACEMENT THERAPY (ERT)

For people with Fabry, ERT is a long-term therapy whereby the missing or deficient enzyme is given via an intravenous infusion. Recent studies looking at improvements of GI symptoms for patients on ERT have shown a reduction in abdominal pain and diarrhoea in females 15 and a reduction in abdominal pain or diarrhoea from weekly occurrences to only occasionally in males who had been on ERT for 6–7 months.

GENE THERAPY

Gene therapy is a way of altering the genetic instructions inside the body’s cells to treat or stop disease. Often, gene therapy works by introducing a correct copy of a defective gene into the patient’s cells, without removing or modifying the defective gene. To get the correct copy into the cells, a new healthy gene is created in a laboratory. The new, healthy gene is placed in a modified (harmless) version of a virus, called a “vector,” to carry the altered genes into the targeted cells. Once in the cell’s nucleus, the new or fixed gene “turns on” to instruct the protein to function properly – by producing a normal protein. The new working gene instructs cells to make the α-Gal A enzyme and release it via the bloodstream for delivery to other organs. Gene therapies are specifically designed to stay in the body for a long time, providing a long-term treatment or cure for a disease instead of simply treating the symptoms.

Multiple gene therapy approaches are being studied as one-time treatments that provide stable, continuous production of α-Gal A to slow or stop the progression of Fabry disease.

Living with difficult physical symptoms is only one of the challenges people with Fabry disease may face. Fabry disease is a rare disease and you may experience feelings of fear, depression, isolation or guilt about passing the disease along. Family members may be affected as well.

Remember that you are not alone.

We give support to newly diagnosed Fabry patients as well as those with a long history of living with the disease. You may find it helpful to talk with someone else from the Fabry International Network – someone in a similar situation with similar concerns and fears.

Please do not hesitate to reach out to us!

Resources & important links

Questions?

Fabry disease is an X-linked genetic disease that is caused by mutations in the GLA gene. The GLA gene generates instructions for an enzyme called alpha-galactosidase A (Alpha-GAL), which is responsible for the breakdown of a type of fat called globotriaosylceramide (Gb3 or GL-3).

Accumulation of Gb3 in the body can cause a wide range of problems, including stroke, kidney disease, and heart attack. (Refer to our “What is Fabry disease?” overview page for more details.)

Fabry disease is estimated to affect one in 40,000 to 60,000 males.

Two main types of Fabry disease have been described: type 1 (classic Fabry disease) and type 2 (atypical or late-onset Fabry disease), depending on when the symptoms appear.

Fabry disease has previously been classified as an X-linked, recessive genetic disorder; however, females who carry the Fabry gene may show signs and symptoms of Fabry disease.

Fabry disease is therefore now described as ‘following X-linked inheritance’ and the use of the term ‘carrier’ for females with the Fabry gene may no longer be appropriate.

Because Fabry is an X-linked disease, it mainly affects men because they have only one X-chromosome. In females, the second, healthy X-chromosome can compensate for the mutated gene. That means women can carry the disease and pass it to their children. Due to the way Fabry disease is inherited, symptoms vary more in women than they do in men. Most men with Fabry disease will experience the full range of symptoms. Symptoms in women can be highly variable, even within the same family. Women with the disease may experience symptoms as severely as men, they may have milder symptoms, or they may have severe symptoms in some organs but not others.

Early diagnosis of Fabry disease is essential so that specific Fabry disease treatment and symptomatic management can be initiated to try to limit potentially irreversible organ damage.

Prompt Fabry disease diagnosis may also benefit relatives of the patient in whom the disease is yet to be diagnosed.

The symptoms of Fabry disease can be wide-ranging including chronic pain, dark red spots on the skin, cloudy eyes, hearing loss, kidney damage, risk of heart attacks, decreased ability to sweat, and more. For more information, refer to our “symptoms of Fabry disease” page.

Genetic counselling is essential to help patients and family members understand the diagnosis and potential Fabry disease treatment options.  Genetic counselling is also helpful to explain the risks, benefits and limitations associated with different genetic tests, and can be used to explain the results of these tests.  Finally, genetic counselling is a valuable opportunity to provide information about patient support groups.

No. Fabry disease is a genetic disease and cannot be acquired from physical contact with an affected individual.

Fabry disease is known to reduce life expectancy by about 20 years when compared to healthy individuals. The average life expectancy for men with Fabry disease is about 58 years in the U.S. compared to 75 years in the case of healthy men.

There is no known cure for Fabry disease, but many of its symptoms can be managed effectively. Available treatments include enzyme replacement. Enzyme replacement therapy is available for all patients. Chaperone therapy is available for patients with a so-called “amenable” α-galactosidase A gene mutation (the specific mutation carried by your patient must be confirmed via genetic testing to ensure that they are eligible for treatment).  Symptoms can be present in organs such as the kidney, heart, and ears. Patients may also have psychosocial issues resulting from diagnosis and disease. Thus, a multidisciplinary approach to Fabry disease treatment is required, and patients will require ongoing symptomatic treatment even after enzyme replacement therapy has been initiated.

Lifestyle and dietary changes also may be needed to further improve quality of life.

FIN regularly publishes articles that cover a range of relevant news, information, and treatment options for patients and caregivers of those with Fabry disease, including ongoing research and upcoming treatments in development.

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