Fabry Disease

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Fabry Disease belongs to a group of inherited metabolic disorders called lysosomal storage disorders which are the result of a deficiency of an enzyme within the lysosomes.

Lysosomes are distributed widely within all the cells of your body. Quite commonly, they are referred to as the digestive system of the cell. They are vital for breaking down substances to either be recycled by the cell or excreted from the body.

Fabry Disease is caused by a problem in the GLA gene.

The GLA gene is needed to provide instructions for an enzyme called alpha-galactosidase A which breaks down globotriaosylceramide. A problem in the GLA gene means not enough of the enzyme is produced and your body is unable to break down globotriaosylceramide. As a result, the substance accumulates within the lysosomes and damages the cells particularly in the kidneys, heart, and nervous system. It consequently leads to the signs and symptoms of this disorder.

There may only be a partial absence of the enzyme which has milder symptoms when compared to the complete absence. However, the milder form is not to be underestimated, as it can still cause damage to vital organs such as the heart and or the kidney

Fabry Disease is thought to affect approximately 1 in 1,000 – 9,000 people. Generally, it affects all ethnicities but men are primarily affected. The late-onset type is estimated to be more common that the classic phenotype.

Males inherit one X chromosome from the mother and one Y chromosome from the father. Females inherit one X chromosome from the mother and another X chromosome from the father. If you are a male and you have a fault in a gene on the X chromosome, symptoms will be more likely to occur. This is because males solely rely on this gene working on the one X chromosome they have. Whereas females, who have two X chromosomes, are less likely to present with symptoms as the other copy of the gene on the second X chromosome is most likely able to compensate for the faulty gene. Although extremely rare, in some cases, a female may end up inheriting two chromosomes that carry the genetic error.

Unlike other X-Linked conditions, Fabry Disease can cause significant health problems in females and they may be affected by the classic signs of this disorder. In some cases, they may be milder or present later in life, but this is not always the case.

Common signs and symptoms include:

• Lack of or reduced ability to sweat (hypohidrosis)
• Episodes of pain, particularly in the hands and feet (acroparesthesias)
• Progressive kidney impairment leading to renal failure
• Cardiac and/or cerebrovascular disease
• Cloudiness in the front part of your eyes
• Nervous system abnormalities
• Ringing in the ears/ hearing loss (also known as tinnitus)
• Abdominal discomfort
• Frequent bowel movements
• Dark red spots on the skin, commonly found in areas between the belly button and your knees (also known as angiokeratomas)
• A low red blood cell count or haemoglobin (also known as anaemia)

This is a progressive disorder, which means that symptoms tend to get worse over time.  Symptoms can cause damage to the brain, kidneys and heart and result in kidney failure, heart failure, and stroke. Most individuals are not diagnosed until adulthood when the symptoms of this condition present. Later in life can in some affected individuals appear the milder form of the disease. It only involves problems with the heart, kidneys, or blood vessels in the brain.

You will be diagnosed after a clinical examination by your specialist or doctor. However, as the signs and symptoms of this disorder are similar to other conditions, you will need further tests. 

 If you are suspected of having Fabry disease your health care provider may carry out a blood spot test. This would involve a small prick on one of your fingers to gain a blood sample to test the levels of the enzyme present within your body. 

 Another test may be performed to check for Fabry Disease, this would be a GLA genetic test. The health care provider would take a swap of your cheek or from another part of the body to test your DNA to check the GLA genes for any errors, this diagnostic tool can be used to test for Fabry disease. 

 Your doctor may also suggest kidney biopsy or MRI.  

 Due to the rarity and similarity of this condition to other medical conditions, Fabry Disease can often be misdiagnosed in young children. 

Treatment which is specifically aimed at managing the individual symptoms continues to play a key role in the management of this condition. The health care professional would prescribe specific drugs tailored to manage symptoms and signs as they appear. These drugs are as follows: 

• Fabrazyme (agalsidase beta) 
• Galafold (migalastat) 
• Low doses of diphenylhydantoin, carbamazepine, or Neurontin 

Fabrazyme (agalsidase beta), is a solution containing the active enzyme. Fabrazyme works by reducing deposits of globotriaosylceramide within the cells of the kidneys and various other vital organs. Extensive research regarding this treatment has been promising, as it has been suggested that by as early as 20 weeks of treatment there can be almost a complete clearance of the substance. Your specialist will prescribe this drug to you and it will be administered via intravenous drip (usually every 2 weeks). Management and dosage will be thoroughly examined and explained by your health care provider. 

Galafold is primarily given to individuals above the age of 16 and is generally administered every other day. This drug works by attaching itself to many unstable forms of the enzyme and transporting them to the lysosome where it should be active in. It can be administered in capsule form once prescribed by your health care professional. If you experience headaches once you have been administered Galafold, do not panic, this is one of the most common side effects of this treatment. 

Diphenylhydantoin, carbamazepine, or Neurontin may help to reduce the pain suffered in the hands and feet (acroparesthesia), other symptoms such as kidney problems should be treated symptomatically. 

Dietary wise, your specialist dietitian may prescribe a low-fat diet to help resolve any gastrointestinal problems that you experience. This means avoiding foods high in fat such as cheese, dairy products, coconut oil and other high fat containing foods, it is recommended to always check the label of the foods you consume if you do suffer with gastrointestinal problems with this condition. 

Chronic kidney problems or kidney failure would require hemodialysis and/or kidney transplant. Other symptomatic management may require rehabilitation, hearing aids or psychological support.  

An early treatment with the enzyme replacement therapy with or without chaperone therapy is advised to prevent or delay kidney, cardiac or cerebrovascular manifestations.  

Fabry Disease is inherited in an X-linked chromosomal manner. This means that one of the X linked sex chromosomes that you inherited has the disorder upon it. With males who only have one of the X sex-linked chromosomes, one altered copy of the GLA gene is enough for symptoms to present. Whereas with females who have two copies of the GLA gene on the two copies of the X sex-linked chromosomes, the person may have a non-functioning GLA gene on one of the chromosomes, but the other X chromosome may be able to provide instructions to make the enzyme and thereby the symptoms would not present or be less severe.  

Males with Fabry Disease pass their X chromosome on to all their daughters. In this way, all daughters of affected males will carry the gene for Fabry disease. This is assuming paternity is not of concern or in question. However, symptoms may not present as the X chromosome inherited from the mother may be able to make up for the non-functioning or absent one. 

Every time a female has a child there is a 50% chance that they will pass the metabolic condition onto their daughter and a 50% chance that you will not. Fathers do not pass the gene onto their sons as they only inherit the Y chromosome from their father. 

Once you are diagnosed, you can speak to a genetic counsellor. They can explain how you may have inherited Fabry Disease. They can also tell you about genetic testing for the rest of your family. They can provide advice and support if you go on to have children of your own. 

References are available on request. Please contact Helen Morris by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: FLY002].