Rare hereditary amyloidosis

By Professor Gilles Grateau – Tenon Hospital PARIS - FRANCE

What are the rare forms of hereditary amyloidosis?

In hereditary amyloidosis, the abnormally (misfolded) protein which accumulates in the body is caused by genetic mutation. The most frequent hereditary amyloidosis is secondary to mutations in the gene the protein transthyretin which mainly attacks peripheral nerves and the heart.

Beside transthyretin amyloidosis, there are several other forms of hereditary amyloidosis caused by the mutation of other proteins. These are the rarest forms of multisystemic amyloidosis, i.e. those which affect several organs.

The proteins involved in these forms are: the alpha chain of fibrinogen, several proteins belonging to the family of apolipoproteins: A1, A2, A4, C2, C3 lysozyme, gelsolin (see table).

Classification of hereditary forms of amyloidosis

Amyloid protein Precusor Name of Amyloidosis
ATTR Mutated Transthyretin Familial amyloidosis
AApoAl Apolipoprotein AI Apolipoprotein AI amyloidosis
AApoAlI Apolipoprotein AII Apolipoprotein AII amyloidosis
AApoAlV Apolipoprotein AIV Apolipoprotein AIV amyloidosis
A β)2M β 2-Microglobin β 2-Microglobin amyloidosis
AGel Gelsolin Gelsolin amyloidosis
Afib Fibrinogen α chain Fibrinogen α chain amyloidosis
Alys Lysozyme Lysozyme amyloidosis
ALect2 Leucocyte chemotactic factor 2 ALect2 Amyloidosis
Acys Cystatin C Cystatin C amyloidosis
Aker Kerato-epithelin Familial corneal dystrophy
Alac Lactoferrin Lactoferrin corneal amyloidosis


How are rare forms of hereditary amyloidosis diagnosed?


These forms are very rare and have no specific clinical characteristics. What is peculiar is the hereditary character of the disease, with the presence of other cases of amyloidosis in the family, in a patient’s ascendants, siblings or children. This distribution is linked to the means of genetic transmission of the disease which is “dominant”. In the presence of several cases of amyloidosis in a family, we should think firstly of transthyretin amyloidosis but also of these rarer forms of the disease.

However, other cases of amyloidosis in the family are not always recognized and, in some cases, the patient may be the only subject affected. We think of these genetic forms after excluding more frequent forms.

Rare forms of hereditary amyloidosis chiefly affect the kidneys. As with other diseases affecting the kidneys, there are no symptoms for a long time. The patient is therefore unaware of his or her condition whereas amyloidosis gradually builds up in the kidneys. The delayed clinical symptoms are swollen ankles, rise in blood pressure and the usual symptoms caused by kidney failure when it is serious (tiredness, pallor, breathlessness, itching).

As we have seen, the disease is often evoked in the presence of a biological anomaly reflecting a kidney condition: the presence of excess protein in the urine and an increase in blood creatinine which defines kidney failure.

Apart from the kidney which is the main target organ, all the other organs can potentially be affected too, depending on the nature of the abnormal protein.

As is the case for all forms of amyloidosis, the diagnosis requires a tissue sample or biopsy taken from an easily accessible tissue like accessory salivary glands or the digestive tract. Indeed, deposits are frequent there whereas no symptoms are present.

However, occasionally, there is no suspicion of amyloidosis because in this case we are faced with the rarest forms of a rare disease. In such cases, it is usually a renal biopsy which is performed, the only way of knowing what is in the kidney.

Then the presence of amyloidosis needs to be confirmed with the Congo Red staining. A more thorough examination of these deposits with specific antibodies (a test only available in a few specialized laboratories) can help the diagnosis when it shows that the deposits are not recognized by the antibodies which react with the most frequently found proteins but are recognised by antibodies which react with the proteins in question in these rare forms.

It is necessary to carry out a survey of the family’s medical history to detect these asymptomatic cases and enable an affected subject to receive genetic counselling is she wishes to have children.

In French law, screening must take place during a genetic consultation, after a prior discussion with a psychologist. It concerns only adults (over eighteen years old). Firstly, the screening will concern the patient’s siblings (brothers and sisters) and any children over eighteen.

The result of the genetic analysis can only be issued after a period of several weeks and several preliminary sessions with the psychologist to prepare the patient for the announcement of the results.

If the result of the genetic test proves negative, the patient has no risk of ever developing the disease, nor will s/he transmit it to children and descendants. If the result is positive, s/he is likely to develop the disease and transmit it to his or her children. In this case a medical check-up is recommended to look for initial signs of the disease (kidney condition).

What is the treatment for rare hereditary amyloidosis?

The treatment consists of two parts.

The first one is the treatment of the kidney condition. When the kidneys no longer function, the patients can be put on dialysis. In most cases, a kidney transplant is possible, but the disease can then affect the transplanted kidney.

But the real purpose of the treatment is to stop the production of the mutated protein which is causing the disease. This can be envisaged when the protein is produced by the liver, as is the case for transthyretin. A liver transplant can then be proposed. Therefore, this treatment can be envisaged in cases of amyloidosis by mutation of the fibrinogen alpha chain. On the other hand, it cannot be carried out in forms linked to the lysozyme, because this protein is produced by numerous tissues.

Evolution and monitoring of rare hereditary amyloidosis

The evolution of these diseases is very variable, notably concerning affected kidneys the functioning of which can worsen slowly or, on the contrary, rapidly. In all cases the kidney disease needs to be monitored.