Who discovered Fabry Disease? Fabry disease or otherwise known as: anderson-fabry disease, angiokeratoma corporis diffusum hereditary dystopic lipidosis alpha-galactosidase A deficiency gla deficiency ceramide trihexosidase deficiency Fabry disease was first identified in 1898 by two dermatologists working independently, Dr William Anderson in England and Dr Johannes Fabry in Germany.1

Dr Johannes Fabry (left) and Dr William Anderson (right).

They separately published papers in which they described patients with skin lesions, known as angiokeratomas, which are now recognised as a common sign of Fabry disease. The disease has a number of names, including angiokeratoma corporis diffusum, alpha-galactosidase A deficiency, and was for many years known as Anderson-Fabry disease, but is now usually referred to simply as Fabry disease. It was not until 1965 that the inheritance pattern was recognised by an American geneticist, Dr. Opitz. The deficient enzyme was first recognised by Dr Roscoe Brady (who pioneered enzyme replacement therapy in Gaucher disease, another lysosomal storage disorder) in 1967, and in 1970 it was specified as α-galactosidase A by Kint and co-workers. The gene was discovered in 1986 by Bishop and co-workers.

What is Fabry Disease? Fabry disease is a rare disorder caused by a defective gene in the body. A person who inherits the abnormal gene or (gene mutation) that causes Fabry disease, cannot produce enough of an important enzyme called alpha- galactosidase A or alpha-A. This enzyme, alpha-A, is needed to clear certain cells in the body of a fatty substance called globotriaosylceramide or GL-3. Since a person with Fabry disease does not produce enough alpha-A, GL-3 is not removed from the body, but instead builds up in the cells.

Vascular Endothelium- GL-3 accumulation

Over many years, GL-3 slowly accumulates and builds up in the walls of blood vessels body fluids and the cells of many tissues, particularly the nerves, kidney, heart and eyes.

Involvement of major organ systems such as the heart, kidney, skin and brain may eventually lead to life threatening problems.

A great visual explanation for this build up of GL-3 in a person with Fabry Disease is the above diagram. (Diagram courtesy of Shire Therapeutics)

A good analogy is a household when the bin bags containing the rubbish produced by the family are filled up and taken outside to the bin. If the bin is not put out for collection, the rubbish will gradually build up over time. Eventually the rubbish 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 GL-3 is broken down and removed from the cells or recycled. However, without the enzyme, Gb2 gradually builds up in the cells and affects their normal function.

References

1. Beck M. Fabry disease: clinical manifestations, diagnosis and therapy; 2007 (2nd edition).
2. Mac Dermot KD, et al. Journal of Medical Genetics 2001; 38: 769-775.

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 births1. Fabry disease can affect all ethnic groups. However, the estimated incidence of lysosomal storage disorders in the Australian population is 1 in 5,000 births.

It is currently estimated that Fabry disease affects approximately 5,000 to 10,000 people worldwide. However, several literature reports suggest that Fabry disease may be significantly under diagnosed, and the prevalence of the disease may be much higher.

Fabry disease can affect anyone who inherits the faulty gene — both males and females. Virtually all males with the Fabry gene develop the disease and are likely to express some or many of the classic Fabry symptoms. In women with the Fabry gene, however, symptoms can range from none (in asymptomatic carriers) to very serious manifestations similar to those seen in males. That’s because the level of symptom severity often depends on the amount of alpha-GAL enzyme produced in the body.

Fabry disease is one of a group of disorders called lysosomal storage disorders. Of these, Fabry disease is the second most common after Gaucher disease2. 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 patients3,4.

References

1. Meikle PJ, et al. Journal of the American Medical Association 1999; 281: 249-254.
2. Fuller M, et al. In: Mehta A, et al (eds). Fabry disease: perspectives from five years of FOS, 2006.
3. Spada M, et al. American Journal of Human Genetics 2006; 79: 31-40.
4. Mehta A, et al. European Journal of Clinical Investigation 2004; 34: 236-242.

Lysosomal Storage Disorder

Lysosomal Storage diseases are inherited genetic defects which result in an enzyme deficiency. The usual effect of this is to prevent the lysosome in the cells of the body from performing its natural recycling function, and various materials are inappropriately stored in the cell. In some of the diseases the enzyme may be present but there are problems with transport of the enzyme into the lysosome, but often causing a similar set of problems.

The diseases lead to a variety of progressive physical and/or mental deterioration over time. Some of the diseases may present in a "mild" form, and others with a more severe impact on the patient. Some patients survive into adulthood, but others with more severe symptoms may die in their teens or earlier.

There are currently more than 45 conditions which come within the category of Lysosomal Storage diseases. There is speculation that many other conditions may have lysosomal storage as their base cause, but the evidence of this is yet to be established for up to 50 other rare conditions.

Lysosomal diseases also exist in atypical forms which may exhibit very different symptoms from the typical form. In the typical form the enzyme will be at very low or undetectable levels, leading to the full set of symptoms, even though these symptoms may present to a mild or severe extent.

In atypical forms there may be a reduced level of enzyme that leads to reduced presentation of symptoms, but possibly significant underlying problems in apparently healthy people. There are also some forms of these diseases that appear later in life, rather than in childhood, such as Late onset Tay-Sachs.

The incidence of LSD's is about 1 in 5,000 live births and the average life expectancy across the whole group is about 15 years.

Further information about LSD's can be found in links section of this website.

Genetics and Fabry Disease

Fabry disease is an inherited disorder. The gene that causes Fabry is passed down from a parent to his or her children. If one person in a family has Fabry disease, other family members (including siblings, children, parents, aunts, uncles, and cousins) may also be at risk. This makes Fabry very much a family disease — not just immediate family, but extended family as well. Fabry disease is considered to be X-linked, which means that the defective gene is located on the X chromosome. To understand this better, it is helpful to understand a little about genetics.

All of our hereditary information is contained on genes. We have genes that determine our physical characteristics like our hair colour, eye colour, sex etc. We also have genes that are responsible for specific functions such as our metabolism and growth.

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 on 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.

Inheriting Fabry Disease

Fabry disease is caused by a mutated gene that does not produce sufficient quantities of the enzyme alpha-galactosidase A (pronounced al-fa-ga-lak-toe-si-daze A) or alpha-GAL. Fabry disease can affect anyone who inherits the defective gene: that means both males and females of any ethnic group. The degree to which a person experiences the symptoms of Fabry disease depends on the amount of alpha-GAL enzyme they have. Females with the defective gene can have anywhere from near normal levels of alpha-GAL to no active enzyme. Males, on the other hand, typically have little to no active alpha-GAL, and can experience more of the classical signs and symptoms of Fabry disease. Therefore, females sometimes experience the same symptoms males do, but not always to the same extent. Fabry disease is inherited, so if one person in a family has the disease, others likely will as well. That is why it is important to develop a medical family tree.