Hereditary brain hemorrhage, or Hereditary Cystatin C Amyloid Angiopathy (HCCAA), is a genetic disorder that is only endemic to Iceland. The disease falls under the category of Cerebral Amyloid Angiopathy (CAA), which is a group of hereditary and sporadic disorders characterized by the deposition of amyloid fibrils/proteins in the walls of cerebral blood vessels. This is a common cause of brain hemorrhages and dementia.

Hereditary brain hemorrhage is inherited in an autosomal dominant pattern and is caused by a mutation in the cystatin C gene (CST3) on human chromosome 20. All carriers of the disease share the same mutation. The disease was first described in 1935 by district physician Árni Árnasen, and to date it has been found in 14 Icelandic families, most of which can be traced to the Westfjords, West Iceland, and South Iceland. It is believed that the mutation originated 18 generations ago, around the year 1500.

The mutation causes the cystatin C protein to become unstable and prone to forming dimers and amyloid fibrils, which are deposited in the blood vessels of the brain. This deposition leads to recurrent brain hemorrhages in very young carriers, which can result in disability, dementia, and death.

Hereditary brain hemorrhage is considered a systemic disease, as it also affects tissues outside the central nervous system. For example, deposition of the cystatin C protein can be seen in the skin, although clinical symptoms are mostly confined to the central nervous system. Connective tissue accumulation is another key feature of the disease and plays an important role in its pathology.

Skin biopsies can be used to monitor disease progression, as the pathological changes seen in skin samples are very similar to those found in brain vessels. Only protein polymers (amyloid fibrils) are deposited—monomers are not. Therefore, it is important to prevent the protein from forming polymers and to inhibit the overproduction of connective tissue proteins.