These disorders are rare and they run in families. They are caused by inheritance of an abnormal copy of a gene, known as a mutation. These mutations lead to life- long production of an amyloidogenic form of a normal protein. The symptoms of hereditary amyloidosis appear in adult life and often only in middle age or later. Some otherwise rare forms of hereditary amyloidosis are common in a few geographic regions around the world, where a few families have intermarried over several generations.
Mutations in the genes for the following normal proteins may cause hereditary systemic amyloidosis, in order from the most to the least common:
- transthyretin (TTR)- ATTR amyloid – over 100 known variants, of which the most common is Familial Amyloid Polyneuropathy (FAP). ATTR amyloidosis is discussed in more detail here.
- fibrinogen – AFib amyloid
- apolipoprotein AI – AApoAI amyloid
- apolipoprotein AII – AApoAII amyloid
- gelsolin – AGel amyloid
- lysozyme – ALys amyloid
- cystatin C – hereditary cerebral haemorrhage with amyloidosis, Icelandic type
- Aβ – hereditary cerebral haemorrhage with amyloidosis, Dutch type
- β2microglobulin – Aβ2m amyloid
Clinical features including organs affected by amyloid, age of disease onset and severity of disease differ widely both between :
- different hereditary amyloidosis types (where amyloid deposits contain different abnormal proteins)
- families with the same hereditary amyloidosis type with different mutations in the same gene, leading to production of different abnormal variants of the same protein.
Disease manifestations may also differ between individuals with the same mutation producing identical variant proteins. Not all individuals who inherit one of these mutations will actually develop clinical problems. Some people with a mutation develop only a small and insignificant amount of amyloid in their body and others seem to accumulate none at all. This is called incomplete penetrance, which is discussed below.
Basic genetics – understanding inheritance
The human body is made up of millions of tiny cells, each of which contains identical copies of the genes which we inherit from our parents. These genes function like an instruction manual, or a recipe book for the cells to construct the proteins and other substances which make up the body. Human cells each contain about 25,000 different genes.
Each cell contains 2 copies of each gene, one from each of our parents. Within each cell, the genes are arranged into forty six long strings, called chromosomes. Twenty three chromosomes come from the father and twenty three from the mother. Complicated interactions between the two copies of each gene determine how the body is composed, inside and out. External traits, like hair colour, eye colour and height and internal traits like blood group are all a consequence of which genes we inherit from our parents. The sex chromosomes determine whether a person is a man or a woman. Women have 2 X chromosomes and men have one X and one Y chromosome in every cell of their bodies. The illustration above shows the chromosomes from the cell of a man.
When a gene is located within one of the sex chromosomes, the way in which it is inherited is called “sex-linked.” Diseases that result from a mutation (abnormality) in a gene within a sex chromosome may be passed from parent to child by “sex-linked” inheritance.
All the other 44 chromosomes apart from the X and Y chromosomes are referred to as “autosomes.” Diseases that result from mutations in genes within the autosomes may be passed on from parent to child by “autosomal dominant ” inheritance or by “autosomal recessive” inheritance.
Most forms of hereditary amyloidosis are inherited by autosomal dominant inheritance.
How do mutations cause amyloidosis?
The genes act like an instruction manual or a recipe for protein production inside every cell of the body.
Sometimes an alteration or error may arise within a gene. This is called a mutation.
Anyone who has ever baked a cake knows that a single error in the recipe may have a number of different effects on the final product. It may lead to complete disaster, for example if you put in salt instead of sugar, or forgot the baking powder. Alternatively, there may be little effect on the final product, for example if you used margarine instead of butter.
Similarly, a mutation in a gene may have a number of different effects. Some mutations have minimal effects or no effects either on the proteins produced or on the person’s health. Other mutations may lead to abnormal protein production, causing a wide variety of diseases.
The mutated genes that cause hereditary systemic amyloidosis have important effects on the abnormal so-called “variant” proteins whose production they determine. The differences in structure between the normal and the amyloidogenic variant proteins are usually extremely small but nonetheless they have very important effects on the behaviour of the variant proteins. In all cases the variants have an increased tendency to clump together and form amyloid fibrils. Thus even a very small change in a gene can lead to serious disease.
Autosomal dominant inheritance
Complex rules control the inheritance of many characteristics, and of many diseases. Hereditary systemic amyloidosis syndromes are inherited in a fashion known as autosomal dominant. This means that the presence of just one copy of a mutated gene can cause the disease.
Autosomal dominant inheritance is illustrated in the figure. The yellow box represents an unaffected gene and the blue box represents an affected gene, carrying a mutation. The two columns next to each person in the figure represent two identical chromosomes (strings of genes) each person inherits, one from each parent.
In the figure, the father has one copy of a mutated gene, and one copy of a normal gene. He therefore suffers from the disease, since, as mentioned above, in this type of disorder, just one copy of a mutated gene is enough to cause disease. The mother, like the vast majority of the population, has two normal genes and is healthy. Each child gets one copy of each gene from their mother, and one from their father.
When there is simple autosomal dominant inheritance of a condition:
- Each child has a 50% (1 in 2) chance of receiving a mutated copy of the gene from the father.
- Each child has a 50% (1 in 2) chance of receiving a normal copy of the gene from the father.
- Half of the children have a mutated gene and develop the disease. They can then pass the mutated gene and the disease on to half of their children.
- Half of the children have two copies of normal gene. They are healthy and they cannot pass the disease on to their children.
- Brothers and sisters of people with the disease have a 50% (1 in 2) chance of having the mutated gene and developing disease.
- Men and women have equal chances of receiving the mutated gene and of developing disease.
For many of the diseases that are passed on by autosomal dominant inheritance, all people with a mutation in the gene develop disease. However, in the case of the hereditary systemic amyloidosis, this is not the case. An additional genetic principle called incomplete penetrance operates, making the situation more complicated. Incomplete penetrance means that:
- Some people who inherit a mutated copy of the gene do not develop any amyloid at all.
- Some people who inherit a mutated copy of the gene develop only a small amount of amyloid and do not suffer from any clinical problems.
- Some patients diagnosed with hereditary systemic amyloidosis have no family history of the disease.
- Information about a particular family is important for evaluation of the likelihood that a young healthy person with a mutation will develop disease.
Genetic testing can be performed at the NAC using a simple blood sample. It usually takes about 4 weeks till results are available. The test involves analysis of all the genes associated with the known forms of hereditary amyloidosis.
Genetic testing is usually offered to patients with amyloidosis that is suspected to be of hereditary type. The genetic test can enable doctors at the NAC to:
- Confirm a diagnosis that has been made by analysis of the proteins in the amyloid deposits.
- Determine exactly what genetic mutation has led to the formation of the abnormal, amyloidogenic protein.
- Gain more information regarding the likely course of disease, in some cases, as different mutations within the same gene are sometimes associated with different disease characteristics.
Healthy individuals with a family member suffering from hereditary systemic amyloidosis may be interested in evaluation of the chance that they themselves will develop the disease. This service is available at the NAC, but only after counselling with one of the physicians. This is important because the issue is not simple, and it is important to understand all the implications of the possible results before deciding whether or not to undergo the test. The NAC welcomes telephone queries on this subject.
The genetic tests can usually determine whether or not the amyloid causing mutation is present. However, even if a mutation is identified, this does not provide clear information about whether and when disease may develop. There are at present no treatments that will delay or prevent disease. The decision of whether or not to undergo testing is therefore a complicated and individual one, involving consideration of a number of psychological and practical issues.