2.1. Danon Disease

There are many mutations in the LAMP2 gene that can cause Danon disease. Danon disease is a condition characterized by weakening of the heart muscle (cardiomyopathy), weakening of skeletal muscles (myopathy), and intellectual disability. This condition affects men more severely than women.

The LAMP2 gene mutations that cause Danon disease lead to the production of very little or no LAMP-2 protein. Most mutations affect all three isoforms of the LAMP-2 protein. However, a mutation that affects only the LAMP-2B isoform also causes Danon disease, suggesting that the condition is caused by defects in the LAMP-2B protein.

Some studies have shown that in cells without the LAMP-2 protein, fusion between autophagic vacuoles and lysosomes occurs more slowly, which may lead to the accumulation of autophagic vacuoles. People with Danon disease have an abnormally large number of autophagic vacuoles in their heart and skeletal muscle cells. It is possible that this accumulation leads to breakdown of the muscle cells, causing the muscle weakness seen in Danon disease.

Some people with LAMP2 gene mutations develop hypertrophic cardiomyopathy without the other characteristic features of Danon disease. Hypertrophic cardiomyopathy is a thickening of the heart muscle that may make it harder for the heart to pump blood. In people with LAMP2 gene mutations, the lower left chamber of the heart, called the left ventricle, is usually the affected region. People with hypertrophic cardiomyopathy caused by LAMP2 mutations often have a particular abnormality of the electrical signals that control the heartbeat called cardiac preexcitation. It is unclear whether this is a separate condition or a milder form of Danon disease. Furthermore, it is unknown why some people with LAMP2 mutations develop hypertrophic cardiomyopathy but not the other features of Danon disease.