General information on hereditary amyloidosis
Hereditary amyloidosis is rare and runs in families. It is 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. There are several different types of hereditary amyloidosis, caused by mutations in different genes.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.