Leigh syndrome affects at least 1 in 40,000 newborns. The condition is more common in certain populations. For example, the condition occurs in approximately 1 in 2,000 newborns in the Saguenay Lac-Saint-Jean region of Quebec, Canada and in approximately 1 in 1,700 individuals on the Faroe Islands.

Leigh syndrome can be caused by mutations in one of more than 75 different genes. In humans, most genes are found in DNA in the cell's nucleus, called nuclear DNA. However, some genes are found in DNA in specialized structures in the cell called mitochondria. This type of DNA is known as mitochondrial DNA (mtDNA). While most people with Leigh syndrome have a mutation in nuclear DNA, about 20 percent have a mutation in mtDNA.

Most genes associated with Leigh syndrome are involved in the process of energy production in mitochondria. Mitochondria use oxygen to convert the energy from food into a form cells can use through a process called oxidative phosphorylation. Five protein complexes, made up of several proteins each, are involved in this process. The complexes are named complex I, complex II, complex III, complex IV, and complex V. During oxidative phosphorylation, the protein complexes drive the production of adenosine triphosphate (ATP), the cell's main energy source, through a step-by-step transfer of negatively charged particles called electrons. Many of the gene mutations associated with Leigh syndrome affect proteins in these complexes or disrupt their assembly. These mutations reduce or eliminate the activity of one or more of these complexes, which can lead to Leigh syndrome.

Disruption of complex I, also called NADH:ubiquinone oxidoreductase, is the most common cause of Leigh syndrome, accounting for nearly one third of cases of the condition. At least 25 genes involved in the formation of complex I, found in either nuclear or mitochondrial DNA, have been associated with Leigh syndrome.

Disruption of complex IV, also called cytochrome c oxidase or COX, is also a common cause of Leigh syndrome, underlying approximately 15 percent of cases. One of the most frequently mutated genes in Leigh syndrome is SURF1. This gene, which is found in nuclear DNA, provides instructions for making a protein that helps assemble the COX protein complex (complex IV). This complex, which is involved in the last step of electron transfer in oxidative phosphorylation, provides the energy that will be used in the next step of the process to generate ATP. Mutations in the SURF1 gene typically lead to an abnormally short SURF1 protein that is broken down in cells, resulting in the absence of functional SURF1 protein. The loss of this protein reduces the formation of normal COX complexes, which impairs mitochondrial energy production.

The most common mtDNA mutation in Leigh syndrome affects the MT-ATP6 gene, which provides instructions for making a piece of complex V, also known as the ATP synthase protein complex. Using the energy provided by the other protein complexes, the ATP synthase complex generates ATP. MT-ATP6 gene mutations, found in approximately 10 percent of people with Leigh syndrome, block the generation of ATP. Other mtDNA mutations associated with Leigh syndrome decrease the activity of other oxidative phosphorylation protein complexes or lead to reduced formation of mitochondrial proteins, all of which impair mitochondrial energy production.

Other gene mutations associated with Leigh syndrome decrease the activity of one or more oxidative phosphorylation protein complexes or affect additional steps related to energy production. For example, Leigh syndrome can be caused by mutations in genes that form the pyruvate dehydrogenase complex or coenzyme Q10, both of which are involved in mitochondrial energy production. Mutations in genes that direct the replication of mtDNA or the production of mitochondrial proteins can also disrupt mitochondrial energy production.

Although the exact mechanism is unclear, researchers believe that impaired oxidative phosphorylation can lead to cell death because of decreased energy available in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles, and heart, seem especially sensitive to decreases in cellular energy. Cell death in the brain likely causes the characteristic lesions seen in Leigh syndrome, which contribute to the signs and symptoms of the condition. Cell death in other sensitive tissues may also contribute to the features of Leigh syndrome.