Leigh syndrome ... (Leigh syndrome) - Genes MT-ATP6 and SURF1

Leigh syndrome is a severe neurological involvement usually arises in the first year of life. In general, this condition is characterized by psychomotor regression and can be fatal due to respiratory failure. A small percentage of individuals do not develop symptoms until adulthood or have symptoms that get worse more slowly.

The first signs of Leigh syndrome usually vomiting, diarrhea and dysphagia, which leads to feeding problems. These problems often lead to growth retardation. Often, affected individuals have severe muscle and movement that may include hypotonia, dystonia and ataxia problems. The, common in people with Leigh syndrome, peripheral neuropathy can also hamper movement. Other signs and symptoms may include additional ophthalmoparesis, nystagmus and optic atrophy. In individuals with the disease, developing severe respiratory problems that can worsen until they cause acute respiratory failure is common. Some affected individuals develop hypertrophic cardiomyopathy. In addition, lactate can accumulate in the body.

Signs and symptoms of Leigh syndrome are caused partly by lesions that develop in certain brain regions of people affected. These regions include the basal ganglia, which help to control the movement; cerebellum, which controls the ability to balance and coordinates movement; and brain stem, which controls functions such as swallowing, breathing, hearing and vision. Often, brain injuries accompanied by demyelination around nerves, reducing the ability of the nerves to activate the muscles used to move or convey sensory information to the brain.

Leigh syndrome can result from mutations in one of more than 75 different genes. In humans, most of the genes found in the nuclear DNA. However, some genes are found in mtDNA. Although most people with Leigh syndrome have a mutation in the nuclear DNA, about 20% have a mutation in mtDNA. Most genes associated with Leigh syndrome are involved in the process of energy production in the mitochondria. Mitochondria use oxygen to convert energy from food in a way that cells can use through oxidative phosphorylation. Five protein complexes, each composed of several proteins are involved in this process. The complexes are called complex I, complex II, complex III, complex IV and V. complex during oxidative phosphorylation, protein complexes direct the production of adenosine triphosphate (ATP), the main energy source of the cell, through electron transfer. Many of the mutations of genes associated with Leigh syndrome affect proteins in these complexes or interrupt their constitution. 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 frequent cause Leigh syndrome, which represents almost a third of cases of the disease. At least 25 genes involved in complex formation I, which are either in nuclear or mitochondrial DNA have been associated with Leigh syndrome.

Disruption of complex IV, also known as Cytochrome c oxidase or COX, is also a common cause of Leigh syndrome, underlying about 15 percent of cases. One of the most frequently mutated genes Leigh syndrome is SURF1 (surfeit 1) gene, located on the long arm of chromosome 9 (9q34.2), encoding a protein that is important in oxidative phosphorylation. The protein contributes SURF1 correct assembly of complex IV, which participates in oxidative phosphorylation. The complex IV, accepts electrons from the previous stages in oxidative phosphorylation. Furthermore, the enzyme accepts protons from inside the mitochondria. Due to the use of electrons and protons, the COX enzyme makes a chemical reaction that converts the oxygen into water. The enzyme also transfers additional protons through specialized within the mitochondria membrane. These processes create energy used to generate ATP, primary energy source of the cell.

SURF1 over 80 different genetic mutations have been identified in people with Leigh syndrome. Approximately 10 to 15 percent of people with Leigh syndrome have a mutation in the gene SURF1. Most mutations result SURF1 gene synthesis abnormally short protein. Other mutations replace a single amino acid in the protein SURF1. The mutated proteins are broken down in the cell, causing an absence of SURF1 protein. The absence of protein SURF1 hinders proper complex formation COX. Consequently, COX activity is drastically reduced, which causes deterioration of oxidative phosphorylation. Although the exact mechanism is unclear, it is believed that impaired oxidative phosphorylation can cause cell death due to the decrease in available energy in the cell. Certain tissues that require large amounts of energy, such as the brain, muscles and heart, seem to be particularly sensitive to declining cellular energy. Cell death in the brain probably gives rise to characteristic changes in the brain seen in Leigh syndrome. Cell death in other sensitive tissues may also contribute to the characteristics of the syndrome.

On the other hand, the most frequent mtDNA mutation in Leigh syndrome affects gene MT-ATP6 (mitochondrially encoded ATP synthase 6), located in the mitochondrial DNA, which encodes a protein that is essential for normal mitochondrial function. The MT-ATP6 protein is a subunit of a enzyme called ATP synthase. This enzyme, also known as the V complex, is responsible for the final stage of oxidative phosphorylation. Specifically, a segment of ATP synthase allows protons to flow through a specialized inside mitochondria membrane. Another segment of the enzyme uses the energy created by the flow of protons to convert adenosine diphosphate (ADP) to ATP.

Mutations in the MT-ATP6 gene found in about 10% of people with Leigh syndrome. These mutations change nucleotides in MT-ATP6 gene. The most common genetic change replaces thymine nucleotide guanine nucleotide by the position in 8993 (T8993G). Mutations in the gene MT-ATP6, alter the function or stability of ATP synthase complex, inhibiting ATP production and damaging oxidative phosphorylation.

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

Leigh syndrome can have different inheritance patterns. Most often it inherited with an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. This pattern of inheritance applies to genes contained in the nuclear DNA, including the gene SURF1. In approximately 20% of people with Leigh syndrome, the disease is inherited mitochondrial pattern, also known as maternal inheritance. This pattern of inheritance applies to genes in mitochondrial DNA, including MT-ATP6 gene. Mitochondrial disorders can appear in each generation of a family and can affect both men and women, but men can not pass mitochondrial traits to their children. Occasionally, mutations in mtDNA occur spontaneously with no history of Leigh syndrome in the family. In a small number of affected individuals with mutations in nuclear DNA, Leigh syndrome is inherited as a recessive X - linked pattern in males, an altered copy of the gene in each cell is sufficient to express the disease. In women, a mutation would have to happen in both copies of the gene to express the disease. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Leigh syndrome, by complete PCR amplification of the exons of the MT-ATP6 and SURF1 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).