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Leigh syndrome is a severe neurological disorder that typically arises in the first year of life. This condition is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within a couple of years, usually due to respiratory failure. A small number of individuals develop symptoms in adulthood or have symptoms that worsen more slowly.
The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and difficulty swallowing (dysphagia) that leads to eating problems. These problems often result in an inability to grow and gain weight at the expected rate (failure to thrive). Severe muscle and movement problems are common in Leigh syndrome. Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). Loss of sensation and weakness in the limbs (peripheral neuropathy), common in people with Leigh syndrome, may also make movement difficult.
Several other features may occur in people with Leigh syndrome. Many affected individuals develop weakness or paralysis of the muscles that move the eyes (ophthalmoparesis); rapid, involuntary eye movements (nystagmus); or degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). Severe breathing problems are common in people with Leigh syndrome, and these problems can worsen until they cause acute respiratory failure. Some affected individuals develop hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. In addition, a substance called lactate can build up in the body, and excessive amounts are often found in the blood, cerebrospinal fluid, or urine of people with Leigh syndrome.
The signs and symptoms of Leigh syndrome are caused in part by patches of damaged tissue (lesions) that develop in the brains of people with this condition. A procedure called magnetic resonance imaging (MRI) reveals characteristic lesions in certain regions of the brain and the brainstem (the part of the brain that is connected to the spinal cord). These regions include the basal ganglia, which help control movement; the cerebellum, which controls the ability to balance and coordinates movement; and the brainstem, which controls functions such as swallowing, breathing, hearing, and seeing. The brain lesions are often accompanied by loss of the myelin coating around nerves (demyelination), which reduces the ability of the nerves to activate muscles used for movement or relay sensory information back to the brain.
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.
Leigh syndrome can be caused by mutations in one of over 30 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. While most people with Leigh syndrome have a mutation in nuclear DNA, about 20 to 25 percent have a mutation in mitochondrial DNA.
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. Five protein complexes, made up of several proteins each, are involved in this process, called oxidative phosphorylation. 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 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 complexes I, II, IV, or V or disrupt the assembly of these complexes. These mutations reduce or eliminate the activity of one or more of these complexes, which can lead to Leigh syndrome.
Disruption of complex IV, also called cytochrome c oxidase or COX, is the most common cause of Leigh syndrome. The most frequently mutated gene in COX-deficient Leigh syndrome is called SURF1. This gene, which is found in nuclear DNA, provides instructions for making a protein that helps assemble the COX protein complex (complex IV). The COX protein 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.
Other nuclear DNA mutations associated with Leigh syndrome decrease the activity of other 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. These mutations lead to a shortage of pyruvate dehydrogenase, an enzyme involved in mitochondrial energy production.
The most common mitochondrial DNA 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 10 to 20 percent of people with Leigh syndrome, block the generation of ATP. Other mitochondrial DNA mutations associated with Leigh syndrome decrease the activity of other oxidative phosphorylation protein complexes or lead to reduced mitochondrial protein synthesis, all of which impair 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.
Changes in these genes are associated with Leigh syndrome.
Leigh syndrome can have different inheritance patterns. It is most commonly inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. This pattern of inheritance applies to genes contained in nuclear DNA. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
In about 20 to 25 percent of people with Leigh syndrome, the condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. Occasionally, mutations in mitochondrial DNA occur spontaneously, and there is no history of Leigh syndrome in the family.
In a small number of affected individuals with mutations in nuclear DNA, Leigh syndrome is inherited in an X-linked recessive pattern. The condition has this pattern of inheritance when the mutated gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
These resources address the diagnosis or management of Leigh syndrome and may include treatment providers.
You might also find information on the diagnosis or management of Leigh syndrome in Educational resources (http://ghr.nlm.nih.gov/condition/leigh-syndrome/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/leigh-syndrome/show/Patient+support).
General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).
To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.
You may find the following resources about Leigh syndrome helpful. These materials are written for the general public.
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).
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You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).
The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.