The reported prevalence of Fabry disease is highly variable and ranges from 1 in 40,000 to 1 in 117,000. However, in certain populations, the prevalence is much much higher. For instance, some studies have found that the prevalence of this condition among newborns in Italy is 1 in 3100, and in Taiwan is 1 in 1500. Late-onset, type 2 Fabry disease is about 10 times more common than classic, type 1 Fabry disease. Fabry disease affects individuals from all ethnicities. Men are affected much more frequently and severely. 

Fabry disease is caused by a mutation in GLA, the gene responsible for encoding the α-Gal A enzyme. Human cells have 23 pairs of chromosomes. Twenty-two pairs are called autosomal chromosomes and are numbered from 1 through 22 while the 23rd pair consists of the sex chromosomes: X and Y. While women have 22 autosomal pairs and two X chromosomes for the 23rd pair, men have 22 autosomal pairs and one X and one Y chromosome for the 23rd. While the gene content of autosomal chromosomes is the same, that is not the case for sex chromosomes. This means that there are many genes on the X chromosome (which is much larger than the Y chromosome) that are not present on the Y chromosome. GLA is one such gene and as a result, it is inherited in an X-linked manner. This means that men that inherited an X chromosome with a defective GLA will develop a more severe form of the disease because there is no functional GLA on their Y chromosome. Women with a defective GLA, on the other hand, have a functional GLA on their other X chromosome and tend to have mild or even no symptoms. 

Affected females tend to have a more variable presentation due to a phenomenon known as random X-chromosome inactivation. Human cells only need one X chromosome to function. Therefore, because women have two X chromosomes, each of their cells randomly inactivates one of the two X chromosomes. In a number of cells, the inactivated cell happens to be the one with the functional GLA, and in the rest, it happens to be the one with the defective GLA. Depending on the number of cells that inactivate the X chromosome with the defective GLA, women may have a milder or more severe presentation.

The X-linked pattern of inheritance of Fabry disease means that men with Fabry disease will pass on the gene to all of their daughters and none of their sons. Women with Fabry disease have a 50% chance of passing on the gene to both their daughters and sons. 

There are close to 1000 different mutations in GLA that can lead to Fabry disease. Some of these mutations will completely obliterate the function of the α-Gal A enzyme, leading to type 1 Fabry disease, and some will only reduce the function of the enzyme, leading to type 2 Fabry disease. Individuals affected by type 1 Fabry disease will begin accumulating Gb3 in small blood vessels from early in life, leading to early disease development and presentation while individuals affected by type 2 Fabry disease will have a slower Gb3 accumulation, and thus, a later disease onset. 

Type 1 Fabry disease

Due to the accelerated nature of type 1 Fabry disease, there are early manifestations associated with this form of the condition which begin in childhood. Symptoms worsen with increasing age due to the progressive accumulation of Gb3 in different body tissues such as the kidneys, the heart, and small blood vessels. These symptoms include:

• Pain in hands and feet (acroparesthesia): This is one of the earliest symptoms of type 1 Fabry disease and is experienced by the majority of affected individuals. It presents at a younger age in boys (2-8 years old) compared to girls. Generally, there are two types of pain experienced by affected individuals. Episodic crises or Fabry crises is a sudden, severe pain in the hands and feet that radiates upwards to the limbs. These episodes which may last from minutes to days can be triggered by stress such as exercise, fatigue, and sudden temperature changes, and is accompanied by fever. In addition to episodic crises, affected individuals also experience chronic pain that is associated with burning and tingling sensations. This symptom usually decreases in severity with age and may completely disappear in some.

• Absent or decreased ability to sweat (anhidrosis or hypohidrosis): Individuals affected by type 1 Fabry disease have an inability to produce sweat, leading to discomfort in warm environments (heat intolerance), or anything that increases the body temperature such as fever or exercise. Almost all affected individuals present with this symptom.

• Reddish to dark blue skin rash (angiokeratoma): Another early sign of Fabry disease is the appearance of skin lesions, mostly in the hip, knee, and genital regions as well as the area around the belly button, that are red to dark blue in color. They may be flat or raised and in clusters or in singly and increase in number and size with age. These lesions are uncommon in type 2 Fabry disease. 

• Gastrointestinal problems: Individuals affected by Fabry disease may experience abdominal pain and cramping, frequent bowel movements, diarrhea, nausea, and vomiting.

• Eye opacity (cornea verticillata): A characteristic presentation of type 1 Fabry disease is an opacity in the cornea, a normally transparent layer covering the font of the eye. It usually has a whorled appearance and cannot be seen without specialized equipment. These opacities do not affect vision.

• Other symptoms: While the symptoms listed above are the most common and characteristic symptoms of Fabry disease, affected individuals may experience other symptoms as well. 

Symptoms common tp type 1 and type 2 Fabry disease

While the symptoms listed above are fairly specific to type 1 Fabry disease, there are symptoms that present later in life, typically in the third to sixth decades of life, and tend to be common to both types. These common symptoms may have an earlier onset in individuals affected by type 1 Fabry disease compared to those affected by type 2. These symptoms include:

• Kidney problems: due to the progressive accumulation of Gb3 in these organs, kidney function deteriorates over time. In type 1, kidney failure almost always occurs while in type 2, it may or may not occur. Kidney failure is the inability of the kidneys to remove waste sufficiently, requiring dialysis or a kidney transplant. 

• Heart problems: The accumulation of Gb3 can affect the heart in different ways. Gb3 accumulates in many different heart-related structures such as heart muscle cells, heart valves that connect the chambers of the heart, heart nerves, and coronary arteries which are the blood vessels that supply the heart itself by oxygenated blood. Fabry disease may lead to the enlargement of the heart that affects the function of heart muscle cells (hypertrophic cardiomyopathy), heart beat irregularities (arrhythmias), and heart failure which describes a condition in which the heart is unable to pump blood efficiently. Symptoms of heart failure include shortness of breath with physical activity or when lying down, fatigue, swelling in the legs, and persistent cough. If the coronary arteries are severely affected, it may lead to myocardial ischemia or myocardial infarction. Myocardial ischemia is when heart muscles do not receive enough oxygen, leading to chest pain and shortness of breath with physical activity that goes away with rest. Myocardial infarction occurs when the oxygen deficit is so extensive that parts of the heart muscle dies, leading to persistent chest pain, pressure, or tightness that might radiate to the left shoulder, arm, the neck, and the jaw. 

• Brain damage: Since Gb3 accumulates in small vessels of the body, it may occlude the small blood vessels in the brain as well. In addition, certain arrhythmias increase the risk of blood clot formation that can circulate the body and occlude other blood vessels. The combination of these factors increases the risk of occlusion of a brain blood vessel which prevents oxygenated blood from reaching certain regions of the brain, causing stroke or less severe brain damages (e.g. transient ischemic attacks). Stroke may present with many different symptoms including sudden numbness or weakness in the face, the arms or legs, particularly on one side of the body, sudden difficulty speaking, sudden confusion, and sudden vision changes. 

• Breathing problems: The accumulation of Gb3 in lung tissue changes the structure of the lungs leading to obstruction of the airways (obstructive lung disease), reduced lung volume (restrictive lung disease), or both. Signs may include shortness of breath, wheezing during either inhalation or exhalation, and coughing.

• Other symptoms: some affected individuals may experience hearing loss or hearing ringing noises (tinnitus), dizziness, or a sense of spinning dizziness (vertigo).

Fabry disease is suspected in males and females who have episodes of severe pain in their hands and feet, red-blue skin lesions, impaired sweating, and characteristic eye opacities, and unexplained heart and kidney problems. The clinical diagnosis of type 1 Fabry disease is easier due to the early manifestations. However, type 2 Fabry disease may present with only non-specific symptoms such as heart and kidney abnormalities. Type 2 Fabry disease is often not diagnosed until later in life when heart and kidney problems begin. In both types, diagnosis is confirmed by showing that the α-Gal A enzyme is deficient and genetic testing confirming and mutation in the GLA gene.

To diagnose Fabry disease, the deficiency of the α-GAL A enzyme is demonstrated. This is done by measuring α-GAL A levels in the blood and/or in white blood cells. Although the results of this test are conclusive in males, this is not the case in females. Females with one defective gene and one functional gene (heterozygous) may have normal enzyme levels. Therefore, diagnosis in females can only be confirmed or ruled out by genetic testing to detect GLA mutations. 

Measuring Gb3 levels in the blood or urine has also been suggested as a diagnostic test for Fabry disease, however, it is not done commonly for diagnosis since this method is more time-consuming and less reliable. However, levels may be correlated to disease severity and help guide management.

Additional tests may be performed to assess damage in other organs. For example, elevated levels of certain molecules such as B natriuretic peptide (BNP) and troponin in the blood can indicate damage to the heart muscle. 

Treatment of Fabry disease consists of management of symptoms as well as enzyme replacement therapy.

• Pain: Medications can be used to control pain associated with Fabry disease. It is important to consider kidney function when selecting the appropriate pain reliever as certain medications can damage a kidney that is already under stress. Additionally, avoiding triggers that are known to cause episodes of pain such as intense exercise and rapid temperature changes can be helpful in pain management. 

• Kidney problems: Blood pressure lowering medications are used to prevent or slow down kidney damage. However, if kidney failure occurs despite medication, dialysis and kidney transplant may be required. Dialysis is a process of removing blood from an individual's body into a tube that circulates through the dialysis machine which acts as an external kidney and removes waste and returning filtered blood back to the body. Dialysis is typically done in a hospital or a clinic, although it can also be done at home in some cases. The frequency and length of dialysis vary depending on the severity of kidney dysfunction but usually, 2-3 times per week, each time for 3-4 hours, is required. A kidney transplant is a procedure in which a donor kidney surgically replaces the affected kidney. Kidney transplant in Fabry disease has better than average outcomes. A successful kidney transplant can correct kidney malfunction.

• Heart problems: In individuals with chest pain after exercise (angina) certain medications such as calcium channel blockers may be given which reduce the force of contraction of the heart and the amount of oxygen that heart muscles need. In individuals with a risk of blood clot formation (e.g. those with certain arrhythmias such as atrial fibrillation), blood thinners may be used to prevent that. Some arrhythmias may require a pacemaker to prevent irregular heart rhythm. If there is evidence of heart failure, diuretics are given to increase urine output and lower blood pressure and volume. This reduces swelling in the legs and fluid accumulation in the lungs which causes coughing. Other medications that lower blood pressure or force of contraction of the heart can also be helpful in heart failure. 

• Enzyme replacement therapy: enzyme replacement therapy is a type of treatment given to individuals who have a deficiency in an enzyme. In Fabry disease, individuals are given a form of α-Gal A. This reduces the accumulation of Gb3 in body tissues and blood vessels and has been shown to slow kidney damage. Although enzyme replacement therapy can improve symptoms, there is little evidence suggesting that it improves long-term outcomes and survival. Enzyme replacement therapy is believed to be most effective if started early before any significant Gb3 accumulation and organ damage has occurred. 

• Chaperone therapy: An oral medication was recently approved that acts as a chaperone meaning that it interacts with, stabilizes, and improves the activity of the defective α-Gal A. This drug can only benefit individuals with certain mutations in the GLA gene. Therefore, genetic testing determines whether or not someone can benefit from this medication. 

The life expectancy of individuals affected by Fabry disease depends on a number of factors. Males with Fabry disease tend to have a lower life expectancy (around 50 years), compared to affected females (around 75 years). Additionally, later diagnosis and treatment initiation can reduce life expectancy.

In addition to reduced life expectancy, Fabry disease is associated with lower quality of life as well. Chronic and severe pain, as well as other accompanying conditions such as kidney and heart problems, have a negative impact on the quality of life. Individuals with Fabry disease experience depression frequently.

Genetics and Rare Disease. Fabry disease. 2018. https://rarediseases.info.nih.gov/diseases/6400/fabry-disease

Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. Published 2010 Nov 22. doi:10.1186/1750-1172-5-30

Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2017 Jan 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1292/