2.1. Nonsyndromic paraganglioma

At least three mutations in the SDHA gene have been identified in people with paraganglioma or pheochromocytoma (a type of paraganglioma), which are noncancerous (benign) tumors associated with the nervous system. SDHA gene mutations are seen most commonly in people with paraganglioma, but they have been found in people with pheochromocytoma. Specifically, SDHA gene mutations are associated with nonsyndromic paraganglioma or pheochromocytoma, which means the tumors are not part of an inherited syndrome.

A single mutation in the SDHA gene increases the risk that an individual will develop the condition. However, an additional mutation that deletes the normal copy of the gene is needed to cause tumor formation. This second mutation, called a somatic mutation, is acquired during a person's lifetime and is present only in tumor cells.

The SDHA gene mutations associated with nonsyndromic paraganglioma or pheochromocytoma change single protein building blocks (amino acids) in the SDHA protein sequence or result in a shortened protein. As a result, there is little or no SDH enzyme activity. Because the mutated SDH enzyme cannot convert succinate to fumarate, succinate accumulates in the cell. The excess succinate abnormally stabilizes HIF, which also builds up in cells. Excess HIF stimulates cells to divide and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the formation of new blood vessels, can lead to the development of tumors.

2.2. Other disorders

Mutations in the SDHA gene have been identified in a small number of people with Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder.

The SDHA gene mutations responsible for Leigh syndrome change single amino acids in the SDHA protein or result in an abnormally short protein. These genetic changes disrupt the activity of the SDH enzyme, impairing the ability of mitochondria to produce energy. It is not known, however, how mutations in the SDHA gene are related to the specific features of Leigh syndrome.