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Fabry disease is a life-threatening and progressive genetic condition that affects the blood vessels, nerves, kidneys, heart, and other organs in both men and women¹. Fabry disease occurs when an individual has a disease-causing mutation (pathogenic variant) in the GLA gene resulting in the body making too little of a specific enzyme called α-galactosidase A¹. The deficiency of this enzyme results in the inability of the body to breakdown some large molecules, in particular globotriaosylceramide (Gb3), which in turn build up in the cells that form blood vessels and other organs¹. The accumulation of these molecules in cells narrows the blood vessels, interferes with cell function, and initiates a generalized inflammatory response².

Fabry disease associated health issues can occur at any age, but based on the timing of the first symptoms manifestation and the combination of the medical issues, the disease is divided into 2 types: classic and non-classic (late-onset) Fabry disease³.

Fabry disease can also be referred to as ^1,2:

• Alpha-Galactosidase A deficiency
• Anderson-Fabry disease
• Angiokeratoma corporis diffusum
• Angiokeratoma diffuse
• Ceramide trihexosidase deficiency
• Fabry's disease
• GLA deficiency
• Hereditary dystopic lipidosis
• Fabry
• Late-onset Fabry disease
• Later-onset Fabry disease
• Classic Fabry disease
• Non-classic Fabry disease
• Fabry disease, Type I
• Fabry disease, Type II

Fabry disease is named after the first doctor, Dr. Johannes Fabry, who described the signs and symptoms of the disease in 1898. Fabry disease is also sometimes referred to as Anderson-Fabry disease, acknowledging another doctor, Dr. William Anderson, who also described its symptoms in 1898¹. Both Drs. Fabry and Anderson were dermatologists, or specialized doctors that treat skin problems. They both had patients with skin lesions common to Fabry disease called angiokeratomas. "Angio" refers to blood vessels and "keratoma" refers to hardened or callous skin. Angiokeratomas look like a painless, red rash and usually appear around the "bathing trunk" area of the body, although almost any area of the body can be affected.².

Classic Fabry disease is the most severe form of Fabry disease. It is found in both men and women. Symptoms begin in childhood including tingling/burning pain in the hands and feet, decreased sweating, overheating or heat intolerance, abdominal pain, and alternating diarrhoea and constipation¹. Eye doctors may also see a "corneal whorl" pattern in children during an eye exam that does not affect vision. The health issues worsen with age leading to extreme tiredness (fatigue), proteins in the urine, a non-itchy reddish-purplish rash (angiokeratoma), depression and ringing in the ears (tinnitus) in the teens and 20s¹. Without treatment, individuals with classic Fabry disease have an increased chance of kidney failure, heart attacks, heart rhythm problems and strokes in adulthood². These health issues can be different from person to person, but typically worsen over time without treatment. There are several medications available to treat Fabry disease, but all of them are most effective when begun early in the disease course, underlining the importance of early diagnosis and treatment³.

Non-classic or late-onset Fabry disease is life-impacting and progressive, but typically does not begin in childhood¹. Often, signs of non-classic Fabry disease are focused on the heart in early adulthood. Heart issues include an enlarged lower left chamber of the heart (left ventricular hypertrophy) and a very thick heart muscle that cannot pump blood out to the body effectively (hypertrophic cardiomyopathy). These heart changes can begin silently without any outward symptoms, but they may also result in chest pain, heart palpitations, shortness of breath, abnormal findings on heart tests like an electrocardiogram (EKG), extra fluid in the legs (oedema), or high blood pressure¹. Some individuals with non-classic Fabry disease will also have kidney problems such as proteins in the urine and/or loss of kidney function¹. These health issues can be very different from person to person, but typically worsen over time without treatment. There are several medications available to treat Fabry disease, but all of them are most effective when begun early in the disease course, underlining the importance of early diagnosis and treatment².

Fabry disease can be associated with a wide range of symptoms, and it is commonly divided into two types, "classic" and "non-classic or late-onset." Both men and women can have either classic or non-classic Fabry disease. Because of the way Fabry disease is passed through families, symptoms often vary more in women than in men. The type of Fabry disease often depends on the age when symptoms start, the organs affected by the disease, how fast the disease progresses, and how severe symptoms become¹.

Classic Fabry disease symptoms in males and females typically start in the first 2-10 years of life with onset of burning pain in the hands and feet, heat intolerance and gastrointestinal issues, such as diarrhoea, pain and constipation². Without treatment, the classic form of the disease progresses into kidney, heart, and other health problems between the ages of 20 to 45³.

In non-classic Fabry disease, symptoms may start after childhood and may more severely affect one organ like the heart or kidneys. It is important to note that heart disease and other symptoms still occur earlier in patients with non-classic Fabry disease compared with average men and women. Therefore, it is important to monitor the heart, kidneys, and brain from the time of diagnosis with Fabry disease. In both classic and non-classic Fabry disease, symptoms typically worsen over time^1,4.

Rarely, classic Fabry disease is referred to as "type I" and non-classic Fabry disease is referred to as "type II", but that is not the preferred terminology.

Fabry disease is caused by changes or mutations in the GLA gene¹. Many of the gene changes are unique to families and to date, there have been approximately 1000 gene changes associated with Fabry disease. The pathogenic variants or mutations in the GLA gene prevent the cells from making enough of a working enzyme called alpha-galactosidase A, or α-GalA. When α-GalA is not working, substances called glycolipids [globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3)] build up in the body's lysosomes (the "recycling centers" of the cell)². This will lead to the narrowing of blood vessels, inflammation, and health problems throughout the body, particularly in the skin, kidneys, heart, brain, intestines, and nerves¹.

Fabry disease is caused by changes or mutations in the GLA gene. The mutations or pathogenic variants in the GLA gene prevent the body from making enough of a working enzyme called alpha-galactosidase A, or α-GalA¹. One of the gene changes often found in Asian populations that is associated with late-onset Fabry disease is a variant of the GLA gene called c.640-801G>A (also known as IVS4+919G>A and c.639+919G>A). The IVS4 gene change is a "splice site" mutation, which means that the gene changes occur at the boundary of an exon and an intron. The change at the splice site can disrupt the reading of the gene by the RNA (ribonucleic acid) to form α-GalA enzyme.

Fabry disease is passed through families in an X-linked inheritance pattern, meaning the GLA gene changes that cause Fabry disease is located on the X chromosome. Women have two copies of the X chromosome (XX) and men have one copy of the X chromosome and one copy of a Y chromosome (XY). If a man inherits an X chromosome containing the non-working GLA gene, then he becomes unable to produce enough working alpha-galactosidase A (α-GalA) enzyme. Without α-GalA, globotriaosylceramide (Gb3) builds up in the cells and causes the symptoms and health problems associated with Fabry disease. On the other hand, if women inherit an X chromosome with a non-working GLA gene, they have a second "back-up" X chromosome with a normal GLA gene, that can produce some working α-GalA enzyme. In the past, it was believed that women who were "carriers" would not have Fabry-related health problems because they have a normal second copy of the gene. However, it is now known that the carrier females can still develop Fabry-related health problems. In some cases, women can have health problems as severe as their male relatives. Since women who carry one copy of the non-working gene can have symptoms of Fabry disease, it is important that they discuss Fabry disease with their doctor and obtain appropriate referrals to monitor their health^2,3.

Women can and do have Fabry disease. If a woman inherits an X chromosome with a non-working GLA gene, she has a second "back-up" X chromosome with a normal GLA gene that may produce some working α-GalA enzyme if it is turned on. In the past, it was believed that women who were "carriers" would not have Fabry-related health problems¹. However, it is now known that the carrier females can still develop Fabry-related health problems. In some cases, women can have health problems as severe as their male relatives. Since women who carry one copy of the non-working gene can have symptoms of Fabry disease, it is important that they discuss Fabry disease with their doctor and obtain appropriate referrals to monitor their health².

Fabry disease is a life-threatening and progressive genetic condition that affects the blood vessels, nerves, kidneys, heart, and other body parts in both men and women. Fabry disease occurs when an individual has a disease-causing mutation (pathogenic variant) in the GLA gene resulting in the body making too little of a specific enzyme called α-galactosidase A (α-GalA)¹. The deficiency of this enzyme results in the inability of body to breakdown some large molecules, in particular globotriaosylceramide (Gb3), which in turn build up in the cells that form blood vessels and other organs¹. The accumulation of these molecules in cells narrows the blood vessels, interferes with cell function, and initiates a generalized inflammatory response².

Fabry disease associated health issues can occur at any age, but based on the timing of the first symptoms manifestation and the combination of the medical issues, the disease is divided into 2 types: classic and non-classic (late-onset) Fabry disease³.

Classic Fabry disease is the most severe form of Fabry disease. It is found in both men and women. Symptoms begin in childhood with tingling/burning pain in the hands and feet, decreased sweating, heat intolerance, abdominal pain, and alternating diarrhoea and constipation. Eye doctors may also see a "corneal whorl" pattern in children during an eye exam that does not affect vision. The health issues worsen with age leading to extreme tiredness (fatigue), proteins in the urine, a non-itchy reddish-purplish rash (angiokeratoma), depression and ringing in the ears (tinnitus) in the teens and 20s. Without treatment, individuals with classic Fabry disease have an increased chance of kidney failure, heart attacks, heart rhythm problems and strokes in adulthood. These health issues can be different from person to person, but typically worsen over time without treatment. There are several medications available to treat Fabry disease, but all of them are most effective when begun early in the disease course, underlining the importance of early diagnosis and treatment^2,3.

Non-classic or late-onset Fabry disease is life-impacting and progressive, but typically does not begin in childhood. Often the main signs of non-classic Fabry disease are focused on the heart in early adulthood. Heart issues include an enlarged lower left chamber of the heart (left ventricular hypertrophy) and a very thick heart muscle that cannot pump blood out to the body effectively (hypertrophic cardiomyopathy)². These heart changes can begin silently without any outward symptoms, but they may also result in chest pain, heart palpitations, shortness of breath, abnormal findings on heart tests like an electrocardiogram (EKG), extra fluid in the legs (oedema), or high blood pressure. Some individuals with non-classic Fabry disease will also have kidney problems such as proteins in the urine or loss of kidney function. These health issues can be very different from person to person, but typically worsen over time without treatment. There are several medications available to treat Fabry disease, but all of them are most effective when begun early in the disease course, underlining the importance of early diagnosis and treatment⁴.

In classic Fabry disease, the early signs usually begin in childhood. Symptoms include tingling or burning pain in the hands and feet, sweating abnormalities, heat intolerance, proteins in the urine, reddish-purple skin lesions called angiokeratomas, chronic tiredness, and gastrointestinal issues, such as chronic diarrhoea, gas, and constipation¹. Usually, the first signs of Fabry disease in kids are a tingling pain in the hands and feet when overheated or sick; frequent bloating, and diarrhoea. Children with non-classic or late-onset Fabry disease most often do not have any of these symptoms. However, the health of children with both classic and non-classic Fabry disease should be monitored even in childhood. Additionally, because of the way that Fabry disease is passed through families, the severity of symptoms and long-term health problems may vary more in girls than in boys².

People living with Fabry disease do not have intellectual impairments or learning problems more frequently than average people without Fabry disease. However, in adulthood they are at higher risk for mini-strokes, TIAs (transient ischemic attacks), and strokes due to the disease's effect on the brain¹. In addition to damage from strokes, some adults with Fabry disease do report symptoms such as "fuzzy thinking," occasional decreased memory for names and dates, and attention deficit issues, even in the absence of stroke damage. There is evidence that some individuals with Fabry disease have issues with executive functioning (verbal generation, reasoning, problem solving, perseveration), information processing speed, and attention from testing, but the exact cause is unknown². Research on brain functioning in Fabry disease has not discovered an accurate method to measure "fuzzy thinking," despite trying through a variety of neurocognitive testing studies¹.

Gastrointestinal (GI) issues in Fabry disease are different from person to person but often include: alternating cycles of chronic diarrhoea and chronic constipation, stomach cramping and pain, bloating, frequent gas, nausea, vomiting, and feeling full early or early satiety¹. Studies have found that 52-60% of patients with classic Fabry disease have GI symptoms². GI issues can start as early as 1 year of age in children with classic Fabry disease. Many people with Fabry disease are also incorrectly diagnosed with Crohn's disease, celiac disease, or irritable bowel syndrome (IBS)³. The GI symptoms in Fabry are thought to be caused by the storage of globotriaosylceramide (Gb3) in the cells that interfere with nerve and cell function in the GI system. This disrupts how fast the stomach empties, how quickly food moves through the intestine, and other functions of digestion including absorbing nutrients⁴. Some individuals with Fabry also find that eating small meals, taking probiotics, and avoiding spicy, lactose-containing, or greasy foods also help to decrease GI issues².

In most cases of classic Fabry disease, boys and girls will present with the same symptoms in childhood. However, because of the way that Fabry disease is passed through families, the severity of symptoms and long-term health problems may vary more in girls than in boys. For this reason, it is important that girls have full medical evaluations regularly to monitor for symptoms¹.

In classic Fabry disease, the early signs for both boys and girls usually begin in childhood and can include overheating or intolerance to hot weather, tingling or pain in the hands and feet, a reddish-purple skin rash, proteins in the urine, and stomach issues, such as frequent bloating or diarrhea². The most common early symptoms of Fabry disease in kids are a tingling pain in the hands and feet when overheated or sick; frequent bloating and diarrhea².

Children with non-classic or late-onset Fabry disease most often do not have childhood symptoms. However, some may also present with some or all of these symptoms and their health should be monitored³.

Patients with Fabry disease may experience psychological symptoms common to other chronic illnesses, including depression and anxiety¹. Appropriate treatment can help most people who suffer from depression. Current treatments include medications and talk therapy with therapists that ease the impact of depression. The first step in determining a treatment path is a psychological evaluation by a psychiatrist and/or a psychologist^2,3. A diagnostic evaluation will include a complete history of symptoms such as: when they started, how long they have lasted, how severe they are, whether the patient had them before and, if so, whether the symptoms were treated and what treatment was given. Some Fabry centers have psychologists skilled in evaluating or treating Fabry-related depression, anxiety, and panic attacks. Individuals with Fabry disease experiencing depression should talk to their doctor about these feelings and ask for a referral for evaluation and treatment².

In some countries, parents can choose to have their babies tested for Fabry disease on their newborn blood test¹. This testing is not available in all countries. To learn more about newborn testing options, patients and families can ask their doctor.

Testing for Fabry disease usually includes an initial enzyme test followed by genetic testing; however, some doctors may be more comfortable referring patients at risk for Fabry disease based on family history or symptoms to a Fabry expert for testing^1,2. The method for testing also varies for males and females.

Disease-specific treatments for Fabry disease include enzyme replacement therapy (ERT) and pharmacological chaperone therapy (for those with certain genetic variants). The goal of ERT is to replace the deficient α-GalA in Fabry disease patients with exogenous enzymes that break down the deposits in the cells that cause health issues¹. On the other hand, the goal of chaperone therapy is to help stabilize the defective α-GalA so that it can break down the Gb3 deposits in the cells that cause health issues^2,3. Discussion with doctors can help patients understand which medications are available in their respective geographical locations.

Treatment for Fabry disease can also include medications that help with disease specific symptoms such as angiotensin-converting-enzyme inhibitor or angiotensin II receptor blocker, which reduce blood pressure or protein levels in the urine. Anti-seizure medications may be prescribed for the pain associated with Fabry disease and medications to treat the gastrointestinal issues may also be prescribed by the physician⁴.

Depending on Fabry symptoms, patients may work with several doctors to find the best treatments and medications to fight the symptoms of Fabry disease.

A cure for Fabry disease would be a one-time treatment that would resolve all medical issues related to Fabry disease. Currently, long-term treatment options are available for Fabry disease, but not a cure¹.

Treatments are being studied to address the underlying causes of Fabry disease that may someday lead to a cure or at least put the disease "into remission". These treatments include gene therapy, which could add or replace the non-working GLA gene in Fabry patients and help the body make its own α-GalA². Other research includes a gene editing technology called CRISPR that would act as a "spellcheck" and correct the changes or mutations in the non-working GLA gene to a working one³.

In order to learn more about treatment and studies looking into a cure for Fabry disease, patients and families can ask their doctor to refer them to a Fabry expert.

It is recommended by the experts and recent opinion-based consensus surveys that the chosen disease-specific therapy should be initiated as early as possible. This is irrespective of the appearance of renal, cardiac, dermatological, gastrointestinal, or neurological signs and symptoms¹. Early intervention with ERT and pharmaco-chaperone therapy may offer protection against complications and health problems related to Fabry disease².

Medical geneticists often have expert knowledge in Fabry disease. These specialists organize the management, monitoring, and treatment of people with Fabry disease. Heart doctors (cardiologists) or kidney doctors (nephrologists) may also be experts who work with patients with Fabry disease¹. In order to find an expert in Fabry disease, patients and families can ask their doctor to refer them to a Fabry expert.

The easiest way to learn more about studies and clinical trials in Fabry disease is to talk to a doctor that specializes in Fabry disease. Patients and families can ask their doctor to refer them to a Fabry expert.

The easiest way to learn about clinical trials in Fabry disease open for people to join is to talk to a doctor that specializes in Fabry disease. Patients and families can ask their doctor to refer them to a Fabry expert.

The best way to learn about gene therapy in Fabry disease is to talk to a doctor that specializes in Fabry disease.

Teachers, particularly physical education teachers and coaches, should be informed about the symptoms of Fabry disease and how your child is functioning physically. The child's teachers should be informed about the medications and special needs of Fabry patients, such as the necessity to avoid overheating during recess or physical education. Make sure that the school has an updated medical documentation and informed expectations if a child with Fabry disease gets ill at school. It is important to emphasize that the children with Fabry disease do not have increased risk for learning disabilities and that Fabry disease cannot "infect" other children¹.

When you feel that your child is mature enough to understand the basics of the disease, you should set aside a time and a place for discussion. Be open to any questions that your child has and be honest about the answers. Ask them to tell you about Fabry disease to make sure they understand and are involved in the conversation. You do not have to tell them everything in one session, since you can always add in more complicated details as your child ages^1,2.

Individuals living with Fabry disease with normally functioning kidneys do not typically need to change their diet. People with reduced kidney function need to be aware that some components of a normal diet may accelerate their kidney failure. Dietitians and kidney doctors can help patients with kidney disease to limit the amount of protein, cholesterol, potassium, and/or sodium they consume so that the kidneys have less work to do¹. Some people with Fabry disease and normal kidney function find that eating small meals, taking probiotics, and avoiding spicy, lactose-containing, or greasy foods also help to reduce gastrointestinal (GI) issues.