ITM2B

Hereditary cerebral amyloid angiopathy

Two variants (also called mutations) in the ITM2B gene have been found to cause a condition called hereditary cerebral amyloid angiopathy. When this condition is caused by variants in the ITM2B gene, it is characterized by movement problems and a decline in intellectual function (dementia). ITM2B gene variants cause two forms of the condition called familial British dementia and familial Danish dementia, named for the regions where the conditions were first diagnosed. The ITM2B gene variant that causes the British type results in the production of a protein that is longer than normal. The ITM2B protein normally has a stop signal that indicates where to stop the protein sequence so that all the ITM2B proteins that are made are the same. The variant that causes the British type changes the stop signal so that more length is added to the protein. This variant is written as Ter267Arg or X267R. The variant that causes the Danish type is similar, but instead of changing the stop signal, extra pieces of DNA are added to the gene, which means that the protein is longer. This variant is written as 795-796insTTTAATTTGT.

The ITM2B gene variants that cause the British type or the Danish type dementia produce elongated precursor proteins, which lead to proteins variants known as ABri or ADan respectively. These proteins have altered 3-dimensional shapes that make them prone to cluster together (aggregate). These aggregated proteins form clumps called amyloid deposits, which accumulate in specific areas of the brain and in its blood vessels. The amyloid deposits trigger activation of the complement system, which is a group of immune system proteins that work together to destroy pathogens, trigger inflammation, and remove debris from cells and tissues. Other immune system reactions are also activated, which all attack the area surrounding the amyloid deposit. The complement system and other reactions lead to cell death and tissue damage in various parts of the brain. These abnormalities underlie the signs and symptoms of the familial British dementia and familial Danish dementia types of hereditary cerebral amyloid angiopathy.