Fabry Disease Description

Further research established that Fabry disease results from abnormal deposits of a fatty substance, known as globotriaosylceramide (Gb3, sometimes abbreviated as GL-3, and also known as ceramide trihexoside [CTH]). Normally, Gb3 is metabolized (broken down) by an enzyme called alpha-galactosidase A (a-Gal A). In people with Fabry disease, the gene that would normally tell the body to produce this enzyme is altered (often called a gene mutation). This alteration means that the enzyme does not work properly or is completely absent. This in turn leads to a build-up of Gb3 in cells of blood vessels, kidneys, brain, eyes and other organs. It is because of this build-up that Fabry disease is referred to as a storage disorder, and because the build-up happens in a part of the cell called the lysosome it is called a lysosomal storage disorder (also known as lysosomal storage disease).

It's a bit like in a household when the trash bags containing the trash produced by the family are filled up and taken outside to the bin. If the bin is not put out for collection the trash will gradually build up over time. Eventually the trash takes up all the space, leaving no room to do anything and causing lots of problems. It is the same principle in human cells - in normal cell function Gb3 is broken down and removed from the cells or recycled. However, without the enzyme, Gb3 gradually builds up in the cells and affects their normal function.

Although there is no cure for Fabry disease, we now know much more about symptoms and how to manage them. Also, research and development continues into therapies that can have a beneficial effect for people with Fabry disease.

Incidence

Fabry disease is a rare condition and it has been estimated that the incidence rate of Fabry disease in the general population is approximately one in 117,000 births. Fabry disease can affect all ethnic groups. The signs and symptoms associated with Fabry disease will almost always be seen in males with this disorder but because of its genetic characteristics, not all females will develop the signs and symptoms. If the signs and symptoms do appear in females it may be at an older age than in males.

Fabry disease is one of a group of disorders called lysosomal storage disorders. Of these, Fabry disease is the second most common after Gaucher disease. However, because the signs and symptoms of Fabry disease are varied, it can take many years to get a confirmed diagnosis. It is therefore thought that there may be many undetected and misdiagnosed patients.

Genetic characteristics

All of the information that makes up a person's physical characteristics such as their sex, height, and their skin, eye and hair color is contained within their genes.

Each cell in the human body contains 23 pairs of chromosomes. It is these chromosomes that hold our genetic 'blueprint'. Each chromosome making up a pair is the same except for the chromosomes that determine a person's sex. These chromosomes are called X and Y. Men have one X chromosome and one Y chromosome (XY) and women have two X chromosomes (XX).

A sperm and an egg contain one chromosome each. A sperm can contain an X or a Y chromosome but an egg contains only an X chromosome. When a sperm containing an X chromosome fertilizes an egg, the child will be a girl (XX). If the sperm contains a Y chromosome, the child will be a boy (XY).

It is the passing of this 'blueprint' in the chromosomes from parents to children that makes Fabry disease a genetic disorder. The gene alteration (often referred to as a 'mutation') that causes the enzyme alpha-galactosidase A (a-Gal A) to malfunction is found in the X chromosome. Therefore, an affected male (XY) will pass the altered gene to all of his daughters but none of his sons. An affected female (XX) will have a 50% chance of passing the altered gene to any child she has, whether they are male or female. Females with Fabry disease may often be referred to as 'carriers' because they have one normal X chromosome and one altered X chromosome.

Lysosomal storage disorders

Fabry disease belongs to a group of disorders known as lysosomal storage disorders (LSDs). Like Fabry disease, many LSDs are named after the people who discovered them, such as Gaucher disease, Hunter syndrome and Hurler disease.

LSDs are a group of over 45 related conditions characterized by defects in lysosomal function due to the inheritance of altered genes.

A lysosome is part of the structure of a cell and is responsible for breaking down certain types of substances so that they can be discarded or reused by the body. These substances are broken down by enzymes in the lysosomes. The altered genes associated with LSDs result in a specific defect in enzyme activity, leading to a build-up of waste substances in body tissue. Many LSDs are similar in character and are usually classified by the type of substance that builds up as a result of the malfunction.

As the substances build-up over time, the symptoms and progression of the disease often become worse. The exact progression of the symptoms depends on the specific disease, its severity and the individual involved. It is also possible that affected members of the same family can show quite different symptoms and at different times.

Currently, the treatment of LSDs tends to be based on the management of symptoms as well as preventing or reversing the decline in organ function.

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Inheritance

Fabry disease is an inherited disorder, with the genetic alteration (called a mutation) being found in the X chromosome.

DNA, the building block of cells, is made up of 23 pairs of chromosomes. The chromosome pair that determines our gender contains either two X chromosomes for a female or an X and a Y chromosome for a male. Daughters (XX) inherit an X chromosome from their mother and an X chromosome from their father. Therefore, all daughters of an affected man will inherit one altered X chromosome from their father and one normal X chromosome from their mother. The presence of one normal and one altered X chromosome means that symptoms of Fabry disease may not appear, or if they do, it will usually be later than in males. The symptoms of Fabry disease may also be less severe, which means females may be more difficult to identify. All of the sons of an affected man will inherit the Y chromosome from their father and the X chromosome from their mother and so will not be affected.

In the situation where it is the mother who has Fabry disease, there is a 50% chance that each child born will also have Fabry disease. If boys inherit the altered X chromosome from their mother, they will develop symptoms, but if they inherit the normal X chromosome from their mother, they will not. If girls inherit the altered X chromosome then they may or may not show symptoms of Fabry disease.

Family History

Many health problems have a genetic link, which means that the level of risk associated with a particular disease or health condition is inherited through our parents. Fabry disease is one such condition.

If Fabry disease has been identified within your family, taking a look at your family's medical history can illustrate who has been affected as well as who is likely to be affected now and in the future. A family tree is also a useful tool for discussing Fabry disease with other family members, your family doctor or your specialist.

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Signs and symptoms

A wide variety of signs and symptoms are associated with Fabry disease. A person with Fabry disease may not experience them all and the severity of symptoms can vary from person to person. This is why Fabry disease can be such a difficult condition to identify and diagnose, although a detailed family history can help. However, as Gb3 builds up, health problems and symptoms tend to get progressively worse.

Although symptoms of Fabry disease will almost certainly be apparent in affected males, females may also have symptoms. Symptoms in females may be no less severe, but they tend to appear at an older age than in males.

Pain

One of the first symptoms, which can occur even in childhood, may be a painful burning sensation in the hands and feet, called acroparesthesia. The pain can be severe and worsen with exercise, stress, illness, and variations in temperature. However, because pain is associated with many ailments, a different diagnosis may initially be given.

Stomach and intestines

Early symptoms of Fabry disease can include abdominal cramps, frequent bowel movements shortly after eating, diarrhea and nausea.

Skin conditions

A common sign is a red, non-painful rash, known as angiokeratoma, which appears usually in the area between the belly button and the knees, but can also appear on other parts of the body such as the lips, tongue, hands and toes. It may be confined to a small area of the body, or may affect a larger area (see examples below).

Individuals with Fabry disease can also experience hypohidrosis or anhidrosis which is a decreased ability, or complete inability, to sweat. This can lead to sensitivity to heat and difficulty in coping with physical exercise. In contrast, some individuals may experience too much sweating (hyperhidrosis).

Eyes

The surface layer of the eye (cornea) may appear abnormal when examined using special equipment that an optician or an eye specialist (ophthalmologist) may have. This appearance, which is called cornea verticillata, does not affect vision but may increase with time. It occurs in approximately three-quarters of patients and can be a reliable indicator of Fabry disease.

Ears

Fabry disease can affect hearing and patients can experience a ringing in the ears that is called tinnitus. Most patients will have some degree of hearing loss at some time and this can either progress over time or be quite sudden.

Kidney

The progressive build-up of Gb3 can lead to kidney problems, with over 80% of people with Fabry disease experiencing some reduction of kidney function. This can lead to an abnormal amount of protein in the urine (proteinuria). Kidney problems are common in males with Fabry disease; however, serious kidney problems are uncommon in females. Severe kidney problems can lead to kidney failure requiring dialysis or transplant.

Heart

Heart abnormalities can include changes in the size of the heart (left ventricular enlargement), irregular heartbeat, and leaky heart valves. Such problems can increase the risk of further heart complications.

Brain and nervous system

Excess Gb3 can disrupt normal blood flow in the brain. This can cause dizziness and in some cases, stroke.

Onset of signs and symptoms

In Fabry disease, Gb3 accumulates over time and so some signs and symptoms may not appear until a person gets older, although symptoms have been reported in children as young as two years old.

Pain, skin rashes, heat intolerance, stomach upsets, fatigue, lack of energy and the inability to exercise are generally the first signs and symptoms to appear, but because these can be associated with other conditions, it may take many years for a diagnosis of Fabry disease to be made. In fact, up to 25% of patients are misdiagnosed.

Kidney, heart and brain problems tend to become noticeable between the ages of 30 to 45 and it is at this point that many individuals with Fabry disease are first diagnosed.

What is particularly concerning about Fabry disease is that there is an average delay between the onset of symptoms and diagnosis of 12 years. This is the same for both sexes, although the onset of symptoms tends to occur about six years later in females than males.

Testing and diagnosis are very important as an early diagnosis is essential for good symptom management. Early diagnosis can also be important in helping to identify other affected family members. It has been shown that the lifespan of a man with Fabry disease is reduced by approximately 20 years and by approximately 15 years for a woman.

Life stages

Because the progression of Fabry disease varies from person to person it also means that symptoms appear at different ages and with differing severity. It is therefore important to consider the different symptoms and to understand the impact of them at different stages of life.

Infants

Of the many symptoms of Fabry disease, it is often pain and heat-related discomfort that appear first in young children with Fabry disease. Parents should therefore be careful not to expose young children with Fabry disease to extremes of temperature.

Children and adolescents

As well as episodes of pain and burning sensations in the hands and feet, children and young people with Fabry disease often develop a spotted, dark red skin rash (angiokeratomas) seen most densely between the belly button and the knees; changes in the appearance of the cornea may also develop and be found by an optician during a routine eye examination when using a special piece of equipment. Parents and teachers should consider the effects of physical exertion, exercise and extremes of temperature on children with Fabry disease. There can also be social-related issues to do with school or employment and it may be useful to consult with specialists about these.

Adults

Fabry disease is slowly progressive and symptoms resulting from damage to the kidneys, heart and central nervous system usually appear between the ages of 30 to 45. In some individuals with Fabry disease it is only when tests are carried out to find the cause of problems with the heart or kidneys that the accumulation of Gb3 is identified and a diagnosis of Fabry disease made. Symptom management can help reduce the effect of symptoms, and lifestyle considerations such as type of employment, choice of leisure activities and diet can all play their part.

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Psychological and quality of life issues

Explaining Fabry disease

Sharing information can help family, friends and work or school colleagues to understand Fabry disease and how it affects someone who has the disease.

Family and friends

Fabry disease is hereditary and so it is important to inform other relatives when there is a diagnosis of previously unknown Fabry disease within a family. These relatives then have the choice of whether to go and see their doctor for a referral to a specialist and, if needed, to undergo testing to confirm whether they too have Fabry disease. This can be a delicate subject, so it may be worth discussing this with your healthcare team or counselor before you approach other family members. Informing relatives and friends about Fabry disease can help them appreciate the needs and treatment of a patient and they can become a useful source of support.

School

Children with Fabry disease can feel different to their friends and classmates, either because of the symptoms they are experiencing or because they aren't able to fully take part in all school activities, for instance sports. Also, they may have to take days off school for hospital visits. If you are the parent or guardian of a child with Fabry disease, explaining the symptoms to your child's teachers will be useful. This should include an explanation of the symptoms, and how physical activities should be monitored to ensure the child is comfortable. In addition, your child may have to take medication during the school day and they may need to be excused from school regularly for hospital appointments and treatment.

Work

You may wish to consider informing your work colleagues if you have Fabry disease, as this will help them to understand the extent of your physical capabilities and that regular absences may be necessary for hospital appointments and treatment.

Family planning

Anyone who has Fabry disease and who wishes to start a family may have concerns about passing Fabry disease on to their children.

Your healthcare team will be an important source of information and support about this and can advise you about pre- and post-natal tests that can be conducted.

A genetic counselor, if you have been referred to one, can be particularly helpful. They may complete a medical family history to assess the presence of Fabry disease within your family. In addition, they can explain the likelihood of your children having Fabry disease, based on your particular circumstances.

Developing a support network

It can be helpful for anyone who has Fabry disease to build a network of support so that they do not feel they have to cope with Fabry disease alone.

In the first instance, it is usually a good idea to be open with family and friends about Fabry disease. Discussing the disease with them will help them to understand the needs of both the patient and their immediate family. Family and friends can be a vital part of any support network. In addition, your healthcare provider may be able to play an important role in supporting your health needs between clinic visits.

As with any ongoing disease, it can be useful to share experiences with people in a similar situation. A number of groups and networks give information and support for people with Fabry disease and their families, including issues such as how to obtain financial support. Importantly, they also provide the opportunity to exchange ideas and encouragement.

Some of these organizations are listed below:

• Society for Mucopolysaccharide Diseases (MPS)
• Fabry Support and Information Group (FSIG)
• Children Living with Inherited Metabolic Disease (CLIMB)

Self-management

While your specialist team will help with treatment, there are some things that patients and caregivers can do themselves to help cope with or manage the symptoms of Fabry disease.

Diet

Gastrointestinal discomfort may be reduced if you eat small, more frequent meals. As with anyone, a healthy diet can contribute to general wellbeing, and a diet that is low in salt can help reduce the risk of heart and kidney problems.

Environment

Pain related to Fabry disease can be triggered by things such as exposure to the sun, sudden changes in temperature, physical exertion or stress. Layering clothing will enable you to adapt to changes in temperature to help keep you more comfortable, whilst drinking plenty of water before and after exercise can help relieve pain related to physical exertion. As stress is a well-documented trigger for pain and other complications, avoiding stressful or emotional situations should be a priority. This may mean planning journeys and allowing time for relaxation and regular naps.

Work

People with Fabry disease should consider an occupation that best suits their lifestyle. A career that requires a great deal of manual skill, rapid changes of temperature, physical exertion or stress should be avoided. As tiredness is a feature of Fabry disease, you should try to allow time for resting during the working day.

School

Children with Fabry disease may feel that they are different from their peers, and they may not be able to fully take part in physical activities. It is therefore useful to make teachers and school friends aware if your child has Fabry disease.

General well-being

Illnesses can trigger pain and worsen symptoms, so regular visits to your doctor to monitor general health are an important part of overall management. As with anyone, it is advisable not to smoke or to drink alcohol in excess to help prevent damage to the heart and kidneys and reduce the risk of stroke.

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 center 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. 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 enzyme testing will miss some affected women. A laboratory genetic test in which DNA is analyzed 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 fetus. This test may be offered to expectant mothers who have Fabry disease. Alternatively, diagnosis can be made by doing gene mutation testing. 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.

After diagnosis

Individuals with Fabry disease may have a number of signs and symptoms that can affect people in different ways; therefore treatment needs to be tailored to the individual. As it is such a rare condition, your healthcare provider may require or request further information from a specialist center that has experience in dealing with Fabry disease. At these centers the patient and their family can be assessed by a range of medical specialists and advised on a specific treatment program.

An on-going program of support with doctors, nursing staff and counselors can also be arranged.

A patient with Fabry may also be asked to participate in what is called either an outcomes survey or a registry. These are records of people with the disease whose progress can be monitored and data collected from around the world to help healthcare professionals better understand the disease and work together to improve patient care in an otherwise uncommon disease.

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Management of Fabry Disease

Management of Fabry often focuses on managing the symptoms of the disease, like pain, skin symptoms, gastrointestinal symptoms, cardiovascular problems, and problems with hearing. In some cases medications or medical procedures or surgery is used. More recently medicines have been used and researched that focus on the genetic causes of the disease. Currently there is no cure for Fabry.

There are two parts of treatment that need to be considered in Fabry disease: the management of symptoms and also the clinical management of the disease itself.

In the first instance, it is important that the different signs and symptoms of Fabry disease are managed to prevent discomfort, and to maintain quality of life. Symptom management will vary on an individual basis, but here is an outline of the types of treatments you might come across:

Pain

Pain is an early and debilitating symptom of Fabry disease. The pain experienced by Fabry patients often does not respond to usual pain relief medication. Those that are more effective at pain relief usually require continuous use and so there are considerations relating to possible side-effects. If the pain is particularly severe, stronger opiate-based pain relief may be necessary. Your physician will advise on the most appropriate pain relief for your particular case. You can also make certain lifestyle choices in order to help minimize painful episodes.

Skin

The skin rashes (angiokeratomas) associated with Fabry disease do not usually cause discomfort, but may bleed in some rare cases. For cosmetic correction, these may be removed with laser treatment.

Gastrointestinal symptoms

The gastrointestinal symptoms of Fabry disease such as diarrhea, vomiting and nausea are similar to those associated with irritable bowel syndrome. To relieve symptoms, drug treatments that speed up the emptying of the stomach may be prescribed. In addition, planning the frequency and type of meals you eat can be helpful in limiting the discomfort.

The kidneys

Because damage to the kidneys can happen quite slowly, the type of treatment will depend on its severity at the time of diagnosis. Regular evaluations should be undertaken to monitor the progress of any kidney damage. Your doctor may also prescribe medications to address your condition. Following a low-sodium, low-protein diet may also help.

If the kidneys are no longer able to function adequately, dialysis may be necessary. This is the process whereby toxins and excess water are removed from the blood artificially with the help of a dialysis machine. In severe cases, a kidney transplant will usually improve the patient's renal (kidney) function, but the Fabry disease itself will still be present in other organs.

The heart

Heart problems can vary in type and severity in Fabry disease. Your doctor may prescribe medication to manage heart symptoms. A variety of drug treatments are available, and your doctor will prescribe the appropriate treatment. If drug treatment is not enough, and symptoms worsen, bypass surgery may be necessary. For severe heartbeat irregularities, a pacemaker may be fitted to help regulate the heart's rhythm. It is highly recommended that if you have Fabry disease you have routine evaluations of your heart as part of your symptom management program.

Stroke

A stroke is essentially what happens when the blood supply to part of the brain is cut off. There are two main causes of stroke. The most common cause is a blockage which happens when a blood clot blocks an artery carrying blood to the brain. This is called an ischaemic stroke. The second type of stroke is called a haemorrhagic stroke and it occurs when a blood vessel in the brain bursts, causing bleeding into the brain. As strokes are potentially life threatening, their prevention is an important part of any management approach for people with Fabry disease. As ischaemic stroke is more common in Fabry disease, anti-blood clotting drugs may be prescribed. There are also a number of self-management choices you can make to help reduce the risk of stroke.

Hearing

Studies show that hearing loss is more common amongst people with Fabry disease than in the general population. Hearing loss is usually gradual, but it has been known to be quite sudden in some patients. Consequently, a hearing aid may be necessary. Tinnitus (ringing in the ears) is also common in Fabry disease.

Who Can Help?

The variety of signs and symptoms associated with Fabry disease means that both its diagnosis and treatment require input from a number of different healthcare specialists.

In the first instance, you may be referred to a specialist center or genetic laboratory for confirmation of the diagnosis. This may be because another member of the family has been diagnosed, or because a certain combination of symptoms may lead your doctor to suspect Fabry disease.

Once a diagnosis of Fabry disease has been made, you may be referred to a specialist center for coordinated consultations and ongoing treatment.

A number of doctors, nurses, therapists and counselors may be involved in the management of Fabry disease:

Healthcare Provider

Your local healthcare provider may have been the person with whom you first discussed your symptoms and who made the initial referral to see a specialist. He or she will also be responsible for your day-to-day health and should be kept informed about the treatments you are receiving at the specialist center.

Specialists in metabolic diseases and lysosomal storage disorders

These are hospital doctors who specialize in diseases that affect how the body makes and breaks down substances. They will also have experience in the genetic side of such diseases. These specialists will often be the doctors who confirm a diagnosis of Fabry disease and co-ordinate a patient's management and treatment.

Geneticist

A geneticist specializes in inherited and genetic diseases. They will often be involved in confirming the initial diagnosis of Fabry disease and may be consulted during the ongoing management program.

Other specialist doctors

As part of your initial check-up at the specialist center, as well as at various times during your care, you may be advised to visit physicians who focus on certain areas. These include (and there may be others):

• Nephrologist — kidneys
• Cardiologist — heart
• Dermatologist — skin
• Ophthalmologist — eyes
• Neurologist — nervous system
• Psychiatrist — mental health

Also, it is possible that it was a physician who specializes in one of these areas who first identified that you may have Fabry disease.

Specialist nurses

You may be assigned a specialist nurse who has expertise in Fabry disease and other lysosomal storage disorders (LSDs). The nurse will potentially be the person with whom patients and their family have the most contact. They may also be responsible for organizing and monitoring treatments.

Counselors

Genetic counseling may be offered, particularly if a person who has been diagnosed with Fabry disease has concerns regarding other family members that may also be affected, or if they are considering starting a family.

Support network

It is also important to develop your own support network, which you can rely on for information and help when you need it.

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