By consultant cardiologist Dr Perry Elliott and research fellow Dr Constantinos O'Mahony, the Heart Hospital, London
Anderson-Fabry disease (AFD) is a rare disease that can affect the heart as well as many other organs. AFD is caused by mutations (spelling mistakes) in the genetic code that determines the make-up and function of cells. The mutations in AFD result in a deficiency of a chemical called a-galactosidase A. This chemical is an enzyme that normally digests fatty material inside cells throughout the body. In its absence, fatty material is not broken down and as a consequence it accumulates leading to swelling of the cells which then stop working properly. Once this happens a variety of symptoms develop. Once AFD is diagnosed, treatment can be instituted to reduce symptoms and complications. More recently, the deficient enzyme has been manufactured artificially and can be administered to patients to correct the deficiency.
The cause of AFD
AFD is caused by a genetic abnormality. Therefore it can run in the families of affected people and can be passed from one generation to the next. The inheritance of AFD is linked to the transmission of the female sex chromosome (known as chromosome X). Women have two X chromosomes (i.e. XX), while men have one X chromosome and one Y chromosome(i.e. XY). Each parent provides one sex chromosome and the resulting combination determines the sex of the offspring. Mutations causing AFD are found on the X chromosome. Women with AFD almost always have one normal X chromosome (Xnormal) and one abnormal X chromosome (XAFD) which carries the mutation. Affected females (Xnormal, XAFD) can pass on the abnormal X chromosome to their children who each have a 50 per cent chance of receiving it. Affected men (XAFD,Y) cannot pass on the disease to their male children, since only the Y chromosome is handed down to produce a male child. However, female children of affected men will always be carriers of the disease since the XAFD from their father is passed on. In women, the normal copy of the X chromosome counter-balances the deficiency caused by the abnormal X chromosome, to a degree. As a result, women tend to develop the disease later in life, and the severity is generally milder. Since affected men have only one X chromosome which is always affected (XAFD,Y) the abnormalities caused are more marked and AFD complications tend to develop earlier in life. So far more than 300 mutations causing AFD have been identified. However, not all mutations are the same and some cause milder disease than others. This means that the severity of AFD is not only related to the sex of the affected individual, but also the type of mutation that runs in that particular family. Other factors can also change the severity of disease but they are not well understood.
The symptoms of AFD
AFD causes a variety of apparently unrelated symptoms, and there is often a delay in reaching the diagnosis. Symptoms generally develop early in childhood and progress with advancing age. Pain affecting the extremities is common, and is often precipitated by exercise, stress, alcohol and other concurrent illnesses leading to acute painful crises. It is caused by the accumulation of fatty material in nerves and the pain often has a “burning” character. Most patients with AFD have abdominal complaints. These include nausea, vomiting, abdominal pain, bloating and diarrhoea which are usually worse after meals. These symptoms develop in childhood and remain troublesome even in adulthood. The majority of affected individuals develop a rash in the “bathing trunk” area between the navel and the knees, and this can spread with ageing to involve other regions. The rash consists of small red spots which are dilated blood vessels called angiokeratomata. Apart from their appearance, angiokeratomata rarely cause significant problems. The nerve supply to the sweat glands is also affected and as a consequence patients can have reduced sweating, and less frequently, excessive sweating. Some patients develop swollen legs, again because of the accumulation of fatty material in the draining system for fluid in the skin.
Small airways in the lungs can also get thickened and cause symptoms similar to asthma such as wheezing, coughing and shortness of breath. AFD patients can eventually develop serious kidney and brain disease. The filtering function of the kidneys becomes affected with leakage of protein into urine. With further deterioration in kidney function, kidney failure may occur, requiring treatment with an artificial kidney machine (dialysis). With advancing age strokes are also common, caused by cut-off of the blood supply to parts of the brain, probably due to fatty material accumulation in the relevant blood vessels. Hearing and balance problems, as well as vertigo are frequently encountered.
The heart in AFD
The heart is commonly affected in AFD. Patients develop chest pain, breathlessness, palpitations and, sometimes, blackouts. These symptoms occur at an earlier age in male patients. The majority of patients have thickening of the heart muscle, called hypertrophy. Hypertrophy becomes more common with increasing age, and is associated with an abnormal heart rhythm tracing (an electrocardiogram or ECG). An abnormal ECG may be the first clue of heart disease in AFD. However, the most important test in determining thickening of the heart muscle is an echocardiogram (commonly known as an echo). This uses special sound waves to determine the thickness and pumping ability of the heart. Hypertrophy contributes to the development of chest pain in some patients. The pain can occur at rest or on exertion and is probably caused by inadequate blood flow to the heart muscle. The pumping function of the heart is typically normal, but the heart muscle can be stiff leading to shortness of breath and sometimes swollen legs. However with time, some patients develop a weak heart muscle causing symptoms. The heart valves can also be affected causing minor leakage but this does not tend to be severe enough to contribute to symptoms. A lot of patients with AFD develop palpitations, an unnatural sensation of the heart beating in the chest. Studies of heart rhythm in AFD have shown that the rhythm can become fast and/or irregular but it can also slow down. This can be associated with a feeling of faintness or even blacking out.
Diagnosis
The diagnosis can be made with a blood test that determines the activity level of the deficient enzyme (agalactosidaseA). Testing for mutations on the X chromosome is an alternative, and is required in females who tend to have low levels of enzyme activity anyway.
Cardiac investigations for AFD
Patients with AFD commonly have the following tests:
Electrocardiogram (ECG): This looks at the way that electricity is conducted in the heart, and may provide clues about the thickness of the heart muscle or the likelihood of developing slow heart rhythms.
Echocardiogram (echo): This provides information about the structure and function of the heart muscle and valves.
24 hour heart monitor (Holter tape): This is similar to an ECG, but provides information over 24 hours. This is useful in patients with troublesome palpitations or blackouts. The duration of the heart monitor can be extended to a few days, if the palpitation is not frequent.
Exercise test: This looks at how well the heart copes with increased demands imposed by exercise. A treadmill or bicycle is used and the heart is monitored with an ECG. The oxygen consumed during exercise can also be measured.
Cardiac magnetic resonance imaging (cardiac MRI or CMR): this test uses a powerful magnet to look at the structure and function of the heart muscle. It is useful in patients where echocardiography is not adequate to visualise the heart clearly.
Coronary angiogram: This provides information about the blood supply to the heart muscle and may be used to exclude coronary artery disease in patients with troublesome chest
Treatment of heart disease in AFD
Treatment of heart symptoms in AFD is similar to other heart diseases. Drugs such as beta-blockers and calcium channel blockers are used to relieve chest pain and shortness of breath. If the heart muscle weakens, then ACE inhibitors and diuretics can be used. In some patients with an irregular heart rate such as atrial fibrillation, which increases the risk of stroke, thinning the blood with warfarin or aspirin is usually recommended. In patients with symptoms caused by a significantly slow heart rate, pacemakers are considered. In some cases where sinister fast heart rhythms are detected, a special pacemaker called a defibrillator can be used to prevent blackouts which may become life-threatening. A defibrillator detects fast heart rhythms and delivers an electric shock to stop them.
Enzyme replacement therapy
Over the past few years the deficient enzyme has been artificially manufactured and can be provided to patients to prevent or even reverse the accumulation of the fatty material in the tissues. This treatment is called enzyme replacement therapy and it is given every two weeks through a drip into a vein. Most patients tolerate this well but a minority may get a mild reaction during the infusion. Enzyme replacement therapy appears to have a good effect on some of the symptoms of AFD and helps with stabilising kidney function. There is some evidence to suggest that enzyme replacement therapy helps to stop further thickening of the heart muscle and prevents slowing of the heart rate and rhythm. There is ongoing research into new treatment strategies in addition to enzyme replacement therapy.
Screening
Since AFD is an inherited disease, once diagnosis is reached in a family member, the rest of the family can be investigated to look for evidence of disease. Identifying AFD in other family members offers the opportunity to provide treatment before the development of complications and allows individuals to take informed decisions about having children.
Summary
AFD is a rare inherited disease, which causes multiple health problems. The heart is commonly affected with thickening of the muscle and rhythm disturbances and most patients develop symptoms such as chest pain, breathlessness and palpitation. Treatment of heart disease in AFD focuses on controlling symptoms and reducing complications with standard medication which is used in other heart problems. More recently, the deficient enzyme has been manufactured and can be give to prevent or even reverse complications.
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Dedicated to Damian McLoughlin, who died age 20 of cardiomyopathy. This site is supported by Damian's family and friends.
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