What are the genetic changes related to hereditary cerebral amyloid angiopathy ?
Mutations in the APP gene are the most common cause of hereditary cerebral amyloid angiopathy. APP gene mutations cause the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont types of this condition. Mutations in the CST3 gene cause the Icelandic type. Familial British and Danish dementia are caused by mutations in the ITM2B gene.  The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the brain and spinal cord (central nervous system). The precise function of this protein is unknown, but researchers speculate that it may attach (bind) to other proteins on the surface of cells or help cells attach to one another. In the brain, the amyloid precursor protein plays a role in the development and maintenance of nerve cells (neurons).  The CST3 gene provides instructions for making a protein called cystatin C. This protein inhibits the activity of enzymes called cathepsins that cut apart other proteins in order to break them down. Cystatin C is found in biological fluids, such as blood. Its levels are especially high in the fluid that surrounds and protects the brain and spinal cord (the cerebrospinal fluid or CSF).  The ITM2B gene provides instructions for producing a protein that is found in all tissues. The function of the ITM2B protein is unclear. It is thought to play a role in triggering the self-destruction of cells (apoptosis) and keeping cells from growing and dividing too fast or in an uncontrolled way. Additionally, the ITM2B protein may be involved in processing the amyloid precursor protein.  Mutations in the APP, CST3, or ITM2B gene lead to the production of proteins that are less stable than normal and that tend to cluster together (aggregate). These aggregated proteins form protein clumps called amyloid deposits that accumulate in certain areas of the brain and in its blood vessels. The amyloid deposits, known as plaques, damage brain cells, eventually causing cell death and impairing various parts of the brain. Brain cell loss in people with hereditary cerebral amyloid angiopathy can lead to seizures, movement abnormalities, and other neurological problems. In blood vessels, amyloid plaques replace the muscle fibers and elastic fibers that give the blood vessels flexibility, causing them to become weak and prone to breakage. A break in a blood vessel in the brain causes bleeding in the brain (hemorrhagic stroke), which can lead to brain damage and dementia.