An Overview of Fabry Disease

Fabry disease is a rare genetic disorder caused by defects in an enzyme that normally digests certain fat-soluble compounds within the body’s cells. These compounds pile up in lysosomes—which are present in cells and all organs—over time and cause harm. Fabry disease can affect many different organs, including the heart, lungs, and kidneys, resulting in a wide range of symptoms.

Fabry disease is considered a lysosomal storage disease and also a sphingolipidosis (a disorder classified by the body's harmful accumulation of lipids). It is passed down through the X chromosome. The disease was first reported in 1898 by Drs. William Anderson and Johann Fabry, and is also known as “alpha-galactosidase A deficiency,” in reference to the lysosomal enzyme that is rendered ineffective by mutations.

Since the condition is rare, a simple suspicion that an individual is suffering from it can lead to diagnostic tests and, in turn, a diagnosis.

Synonyms of Fabry Disease:

• Alpha-galactosidase A deficiency
• Anderson-Fabry disease
• Angiokeratoma corporis diffusum
• Diffuse angiokeratoma
• Ceramide trihexosidase deficiency
• GLA deficiency

Symptoms

The age at which symptoms develop, as well as the specific symptoms themselves, can vary depending on the type of Fabry disease. In classic Fabry disease, the earliest symptoms appear during childhood or adolescence and follow somewhat of a predictable progression of symptoms and manifestations through a person's life. However, individuals with Fabry disease may not develop all of these symptoms.

Early signs of Fabry disease include nerve pain in the hands and feet, and small, dark spots on the skin, known as angiokeratomas. Later manifestations may involve the nervous system, a reduced ability to sweat, the heart, and kidneys. Some individuals have a non-classic form of Fabry disease in which symptoms do not emerge until much later in life and involve fewer organs.

Childhood/pre-teen to teen Years:

• Pain, numbness, or burning of the hands or feet
• Telangiectasias, or "spider veins," on ears or eyes
• Small, dark spots on the skin (angiokeratoma), often between the hips and the knees
• Gastrointestinal problems that mimic irritable bowel syndrome, with abdominal pain, cramping, and frequent bowel movements
• Clouding of the cornea of the eye, or corneal dystrophy, that is detectable by an ophthalmologist and generally does not impair vision 
• Puffy upper eyelids
• Raynaud phenomenon

Young adulthood:

• Bigger telangiectasias
• More angiokeratomas, or small dark spots on the skin
• Decreased ability to sweat and difficulty regulating body temperature
• Lymphedema, or swelling in the feet and legs

Adulthood, mid-life, and beyond:

• Heart disease, arrhythmias, and mitral valve problems
• Kidney disease
• Strokes
• Multiple sclerosis-like symptoms, i.e., spotty nervous system symptoms

Over time, Fabry disease can result in a heart condition known as restrictive cardiomyopathy, in which the heart muscle develops a type of abnormal stiffness. While the stiffened heart muscle can still squeeze or contract normally and thus can pump blood, it becomes less and less able to relax completely during the diastolic, or filling, phase of the heartbeat. The restricted filling of the heart, which gives this condition its name, causes the blood to back up as it tries to enter the ventricles, which can produce congestion in the lungs and in other organs.

As patients with Fabry disease get older, damage to small blood vessels may also provoke additional problems such as reduced kidney function. Fabry disease can also cause a problem in the nervous system known as dysautonomia. These problems with the autonomic nervous system, in particular, are responsible for the difficulty regulating body temperature and inability to sweat that some people with Fabry disease experience.

Symptoms in Females

It is possible for females to be as severely affected as males, but because of the X-linked genetics of Fabry disease, males are more often severely affected than females.

Females with one affected X chromosome may be asymptomatic carriers of the disease, or they may develop symptoms, in which case the symptoms are usually more variable than in males with classic Fabry disease. Of note, it has been reported that women with Fabry disease may often be misdiagnosed as having lupus or other conditions.

In more severe cases, females can have a “classic-like Fabry syndrome,” which is thought to occur when the normal X chromosomes are randomly inactivated in the affected cells.

Other Symptoms

People with classic Fabry disease may have other symptoms, including lung symptoms, chronic bronchitis, wheezing, or trouble breathing. They may also have problems with bone mineralization, including osteopenia or osteoporosis. Back pain primarily in the area of the kidneys has been described. Ringing of the ears, or tinnitus, and vertigo may occur in people with Fabry syndrome. Mental illnesses, such as depression, anxiety, and chronic fatigue, are also common.

Causes

For people affected by Fabry disease, the problem begins in the lysosomes. Lysosomes are those tiny bags of enzymes within cells that help do the job of digesting or breaking down biologic substances. They help to clean up, dispose of, and/or recycle material that the body is otherwise unable to break down and that would otherwise build up in the body.

Lysosomal Enzyme Deficiency

One of the enzymes that lysosomes use to digest compounds is called alpha-galactosidase A, or alpha-Gal A. In Fabry disease, this enzyme is defective, so Fabry disease is also known as alpha-Gal A deficiency. This enzyme normally breaks down a specific type of fat, or sphingolipid, called globotriaosylceramide.

In general, it is possible for an enzyme to have a defect and still perform some of its normal function. In Fabry disease, the better this defective enzyme is able to get by at doing its job, the less likely the person is to have symptoms. It’s thought that, in order to have symptoms of Fabry disease, the enzyme’s activity has to be reduced to about 25% of normal function.

Fabry Disease Variants

Different forms of Fabry disease are known to occur based on how well or poorly the defective enzyme functions. In people who have what is now called “the classic form” of Fabry disease, the defective enzyme really doesn’t function much at all. This results in the buildup of sphingolipids in a wide variety of cells, thus causing compounds to be deposited in a wide variety of tissues, organs, and systems. In such cases of profound enzyme deficiency, cells can’t break down glycosphingolipids, particularly globotriaosylceramide, which builds up over time in all organs, causing cellular damage and injury associated with Fabry disease.

Atypical or Later-Onset Fabry Disease

In other forms of Fabry disease, the enzyme still functions part-time, or with activity that is about 30% of normal. These forms are known as “atypical Fabry disease,” or “later-onset Fabry disease,” and they may not come to medical attention until a person has reached their 40s, 50s, or even decades later. In these cases, there are still damaging effects, often in the heart. As such, the disease is sometimes discovered accidentally in someone who is being evaluated for unexplained heart problems.

Pattern of Inheritance

Fabry disease is inherited in an X-linked manner, meaning the mutated or defective gene is located on the X chromosome. The X and Y chromosomes are probably best known for their role in determining a baby’s gender as male or female. Females have two X chromosomes while males have one X chromosome and one Y chromosome. However, the X and Y chromosomes have many other genes on them in addition to those that determine the sex of a child. In the case of Fabry disease, the X chromosome carries the defective gene which encodes the enzyme, alpha-Gal A.

Men with Fabry disease pass their X chromosome to all of their daughters such that all daughters of affected men will carry the gene for Fabry disease. Affected men do not pass the Fabry disease gene to any of their sons, because sons, by definition, receive their father's Y chromosome and cannot inherit Fabry disease from their father.

When a woman with the Fabry gene has a child, there is a 50:50 chance she will pass her normal X chromosome to the child. There is also a 50% chance that each child born to a woman with the Fabry gene will inherit the affected X chromosome and have the Fabry gene. Fabry disease is believed to affect about 1-in-40,000 to 60,000 males, while in females, the prevalence is unknown.

Diagnosis

Since Fabry disease is rare, diagnosis begins with having the suspicion that an individual is suffering from it. Symptoms such as nerve pain, heat intolerance, decreased ability to sweat, diarrhea, abdominal pain, dark skin spots, and foamy urine may be suggestive of Fabry disease.

Clouding of the eye’s cornea, swelling or edema, and abnormal heart findings may also be clues. A history of heart disease or stroke, in the context of Fabry disease, can also be a consideration in those who are diagnosed later in life.

Then, the diagnosis is confirmed using a variety of tests, potentially including enzyme tests and molecular or genetic testing. In the case of those with a family history suggestive of Fabry disease—unexplained gastrointestinal symptoms, extremity pain, kidney disease, stroke, or cardiac disease in one or more family members—screening the entire family may be helpful.

Enzyme Testing

In males suspected of having Fabry disease, blood can be drawn to determine the level of alpha-Gal A enzyme activity in white blood cells, or leukocytes. In patients with a type of Fabry disease that mostly involves the heart, or the cardiac variant of Fabry disease, the leukocyte alpha-Gal A activity is usually low but detectable, whereas, in patients with classic Fabry disease, enzyme activity may be undetectable. This enzyme test will not detect about 50% of the cases of Fabry disease in women who have just one copy of the mutated gene and may not detect cases in males with variants of Fabry disease. However, genetic testing is still advisable in all cases to determine as much information as possible.

Genetic Testing

Analysis of the alpha-Gal A gene for mutations is performed to confirm the diagnosis of Fabry disease in both males and females. Routine genetic analysis can detect a mutation, or sequence variant, in more than 97% of males and females with abnormal alpha-Gal A activity. To date, hundreds of different mutations in the alpha-Gal A gene have been found.

Biopsy

Biopsy from the heart is generally not required in people with heart problems associated with Fabry disease. However, this might sometimes be done when there are problems with the left ventricle of the heart and the diagnosis is unknown. In these cases, pathologists would look for signs of glycosphingolipid deposition on the cellular level. In some cases, other tissues may be biopsied, such as the skin or kidneys. In very rare cases, Fabry disease has been diagnosed incidentally when doctors have conducted biopsies looking for causes of organ failure (most commonly kidney failure).

Treatment

There are a variety of treatments used for Fabry disease including enzyme replacement therapy—now there is even a newer drug on the market designed to stabilize the body's enzyme.

Enzyme Replacement Therapy

Alpha-galactosidase A (alpha-Gal A) is the enzyme that is deficient in patients with Fabry disease, and the treatment of patients with the disease mainly involves replacing this missing or deficient enzyme.

Males with classic Fabry disease are often given enzyme replacement therapy beginning in childhood or as soon as they are diagnosed, even when symptoms have not yet begun.

Female carriers and males with atypical Fabry disease, or the later onset types of Fabry disease, for whom a solid level of enzyme activity is preserved, may benefit from enzyme replacement if Fabry disease begins to take shape clinically—that is, if reduced enzyme activity affects the heart, kidneys or nervous system. Contemporary guidelines state that enzyme replacement should be considered and is appropriate once there is evidence of injury to the kidney, heart, or central nervous system attributable to Fabry disease, even in the absence of other typical Fabry symptoms.

The Food and Drug Administration (FDA) has approved Replagal (agalsidase alfa), Fabrazyme (agalsidase beta), and Elfabrio (pegunigalsidase alfa) for the treatment of Fabry disease. Although they have not been compared side-by-side in studies, they seem to work equally well. These are intravenous drugs that must be infused every two weeks.

Pediatric guidelines cite the importance of early enzyme replacement therapy in children with Fabry disease, stressing that such therapy should be considered in males with classical Fabry disease before adulthood, even if they don't show symptoms.

Other Treatments

People with Fabry disease receive treatment for problems with their kidneys, heart, and nervous system, as well as other complications of Fabry disease-induced injury to the tissues.

A newer drug called Galafold (migalastat) has been shown to help some aspects of the course of Fabry disease in a subset of patients with “suitable” mutations. The drug works by stabilizing the body's own dysfunctional alpha-Gal A enzyme, helping it find its way to the lysosome and work more normally in patients who have suitable mutations. Galafold is the first helpful oral drug in some people with Fabry’s disease, and the FDA approved Galafold for suitable patients with Fabry disease.  There is a test that determines whether or not a person’s defective enzyme can be helped by Galafold.

A Word From Verywell

It is important to know that Fabry disease is very rare, but it is also often misdiagnosed, given its wide range of nonspecific signs and symptoms. Because Fabry disease is so rare, doctors may not think of it right away in routine practice.

There is an old adage along the lines of the following: when you hear hoofbeats, think of horses, not zebras. A zebra, in American medical slang, refers to making an exotic diagnosis when a simple, more common diagnosis also fits. In patients with Fabry disease, it is not surprising, then, that an initial misdiagnosis or two with some other condition is common. A wide range of initially considered diagnoses in patients with Fabry disease have been reported in surveys on the subject.