Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). The signs and symptoms of this disorder most often appear in childhood following a period of normal development, although they can begin at any age. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).

Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, and hormonal imbalances.

MELAS can result from mutations in one of several genes, including MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV. These genes are found in the DNA of cellular structures called mitochondria, which convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA, known as mitochondrial DNA or mtDNA.

Some of the genes related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex in mitochondria that helps convert oxygen, fats, and simple sugars to energy. Other genes associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

Normal Function

The MT-ND1 gene provides instructions for making a protein called NADH dehydrogenase 1. This protein is part of a large enzyme complex known as complex I, which is active in mitochondria. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. These cellular structures produce energy through a process called oxidative phosphorylation, which uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source.

Complex I is one of several enzyme complexes necessary for oxidative phosphorylation. Within mitochondria, these complexes are embedded in a tightly folded, specialized membrane called the inner mitochondrial membrane. During oxidative phosphorylation, mitochondrial enzyme complexes carry out chemical reactions that drive the production of ATP. Specifically, they create an unequal electrical charge on either side of the inner mitochondrial membrane through a step-by-step transfer of negatively charged particles called electrons. This difference in electrical charge provides the energy for ATP production.

Complex I is responsible for the first step in the electron transport process, the transfer of electrons from a molecule called NADH to another molecule called ubiquinone. Electrons are then passed from ubiquinone through several other enzyme complexes to provide energy for the generation of ATP.

Health Conditions Related to Genetic Changes

Leber hereditary optic neuropathy

Several mutations in the MT-ND1 gene are known to cause Leber hereditary optic neuropathy. Each of these mutations changes a single DNA building block (nucleotide) in the gene. One common MT-ND1 mutation is responsible for about 13 percent of all cases of Leber hereditary optic neuropathy. This mutation replaces the nucleotide guanine with the nucleotide adenine at gene position 3460 (written as G3460A). This change is associated with moderately severe cases of Leber hereditary optic neuropathy; however, 20 percent to 40 percent of people with vision loss due to this mutation experience some recovery of vision.

Researchers are investigating how mutations in the MT-ND1 gene lead to Leber hereditary optic neuropathy. These genetic changes appear to disrupt the normal activity of complex I in the mitochondrial inner membrane, which may affect the generation of ATP. MT-ND1 mutations also may increase the production within mitochondria of potentially harmful molecules called reactive oxygen species. It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MT-ND1 mutations are a rare cause of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Most cases of MELAS are caused by mutations in other mitochondrial genes, but a small number of cases resulting from mutations in the MT-ND1 gene have been reported. Fewer than five mutations, each of which alters a single DNA building block (nucleotide) in the gene, have been identified in affected individuals. These genetic changes reduce the activity of complex I, which disrupts energy production within mitochondria. Although these abnormalities have the greatest impact on tissues that require a lot of energy (such as the brain and muscles), researchers have not determined how changes in the MT-ND1 gene lead to the specific signs and symptoms of MELAS.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Mitochondrial complex I deficiency

MedlinePlus Genetics provides information about Mitochondrial complex I deficiency

Other disorders

A mutation in the MT-ND1 gene has been reported in a few cases of adult-onset dystonia. Dystonia is a movement disorder that involves involuntary tensing of the muscles (muscle contractions), tremors, and other uncontrolled movements. The MT-ND1 mutation associated with these rare cases replaces the nucleotide adenine with the nucleotide guanine at gene position 3796 (written as A3796G). Further studies are needed to determine whether this genetic change combines with other genetic and environmental factors to increase the risk of developing adult-onset dystonia.

Other Names for This Gene

• mitochondrially encoded NADH dehydrogenase 1
• MTND1
• NADH dehydrogenase 1
• NADH dehydrogenase subunit 1
• NADH-ubiquinone oxidoreductase chain 1
• NADH-ubiquinone oxidoreductase, subunit ND1
• ND1
• NU1M_HUMAN

Genomic Location

Normal Function

The MT-ND5 gene provides instructions for making a protein called NADH dehydrogenase 5. This protein is part of a large enzyme complex known as complex I, which is active in mitochondria. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. These cellular structures produce energy through a process called oxidative phosphorylation, which uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source.

Complex I is one of several enzyme complexes necessary for oxidative phosphorylation. Within mitochondria, these complexes are embedded in a tightly folded, specialized membrane called the inner mitochondrial membrane. During oxidative phosphorylation, mitochondrial enzyme complexes carry out chemical reactions that drive the production of ATP. Specifically, they create an unequal electrical charge on either side of the inner mitochondrial membrane through a step-by-step transfer of negatively charged particles called electrons. This difference in electrical charge provides the energy for ATP production.

Complex I is responsible for the first step in the electron transport process, the transfer of electrons from a molecule called NADH to another molecule called ubiquinone. Electrons are then passed from ubiquinone through several other enzyme complexes to provide energy for the generation of ATP.

Health Conditions Related to Genetic Changes

Leigh syndrome

Variants (also called mutations) in the MT-ND5 gene have been identified a few people with Leigh syndrome. Children with this condition 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. A few children with Leigh syndrome caused by MT-ND5 gene variants have had additional features that are not typical of Leigh syndrome, including slow growth before birth (intrauterine growth retardation) and distinctive facial features.

The MT-ND5 gene variants responsible for Leigh syndrome change single DNA building blocks (nucleotides) in the gene. These genetic changes disrupt the activity of complex I, impairing the ability of mitochondria to produce energy. It is not known, however, how variants in the MT-ND5 gene are related to the specific features of Leigh syndrome.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Variants in the MT-ND5 gene are responsible for a small percentage of all cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This condition affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy).

The MT-ND5 gene variants that cause MELAS alter single nucleotides in the gene. Most people with MELAS caused by MT-ND5 gene variants have the variant that replaces the nucleotide guanine with the nucleotide adenine at gene position 13513 (written as G13513A).

Most commonly, MT-ND5 gene variants that cause MELAS have been shown to reduce the activity of complex I, which disrupts energy production within mitochondria. Although these abnormalities have the greatest impact on tissues that require a lot of energy (such as the brain and muscles), researchers have not determined how changes in the MT-ND5 gene lead to the specific signs and symptoms of MELAS.

Variants in the MT-ND5 gene also have been identified in patients with the major features of MELAS in combination with other mitochondrial diseases. For example, researchers have found MT-ND5 gene variants in several individuals with the signs of MELAS and some features of Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. In other cases, people with MELAS and a change in the MT-ND5 gene have developed sudden, progressive vision loss characteristic of an eye disease called Leber hereditary optic neuropathy. A few individuals have been reported with signs and symptoms of all three of these mitochondrial conditions—MELAS, Leigh syndrome, and Leber hereditary optic neuropathy.

It is unclear why changes in the MT-ND5 gene can cause such a large variety of signs and symptoms. Even within a single family, affected individuals may have different health problems caused by the same genetic change.

Mitochondrial complex I deficiency

MedlinePlus Genetics provides information about Mitochondrial complex I deficiency

Other Names for This Gene

• mitochondrially encoded NADH dehydrogenase 5
• MTND5
• NADH dehydrogenase subunit 5
• NADH-ubiquinone oxidoreductase chain 5
• NADH-ubiquinone oxidoreductase, subunit ND5
• NADH5
• ND5
• NU5M_HUMAN

Genomic Location

Normal Function

The MT-TH gene provides instructions for making a particular type of RNA, a molecule that is a chemical cousin of DNA. This type of RNA, called transfer RNA (tRNA), helps assemble protein building blocks known as amino acids into full-length, functioning proteins. The MT-TH gene provides instructions for a specific form of tRNA that is designated as tRNAHis. During protein assembly, this molecule attaches to a particular amino acid, histidine (His), and inserts it into the appropriate locations in the growing protein.

The tRNAHis molecule is present in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Through a process called oxidative phosphorylation, mitochondria use oxygen, simple sugars, and fatty acids to create adenosine triphosphate (ATP), the cell's main energy source. The tRNAHis molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

Health Conditions Related to Genetic Changes

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

A small number of people with the features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) have a mutation in the MT-TH gene. This condition is characterized by recurrent severe headaches, muscle weakness (myopathy), hearing loss, stroke-like episodes including a loss of consciousness, seizures, and other problems affecting the nervous system. Some people with an MT-TH gene mutation also have features of another mitochondrial disorder called myoclonic epilepsy with ragged-red fibers (MERRF); these additional features can include muscle twitches (myoclonus), difficulty coordinating movement (ataxia), and abnormal muscle cells known as ragged-red fibers. This combination of signs and symptoms is called MERRF/MELAS overlap syndrome.

MT-TH gene mutations that cause MELAS and MERRF/MELAS overlap syndrome change single DNA building blocks (nucleotides) in the gene. Researchers have not determined how these genetic changes alter energy production in mitochondria or cause the varied signs and symptoms of MELAS or MERRF/MELAS overlap syndrome.

Myoclonic epilepsy with ragged-red fibers

As mentioned above, a few individuals with a mutation in the MT-TH gene have features of both myoclonic epilepsy with ragged-red fibers (MERRF) and MELAS. The mutation involved in this overlap syndrome replaces the nucleotide guanine with the nucleotide adenine at gene position 12147 (written as G12147A). It remains unknown why this mutation causes the overlapping features of MERRF and MELAS.

Other disorders

Another mutation in the MT-TH gene may increase the risk of developing a heart condition called cardiomyopathy. People with cardiomyopathy have a weakened heart muscle that is unable to pump blood effectively. A particular change in the MT-TH gene has been identified in several adults with cardiomyopathy, but without other common signs of mitochondrial disease such as neurological abnormalities. This mutation replaces the nucleotide guanine with the nucleotide adenine at gene position 12192 (written as G12192A). It is unclear why this alteration in mitochondrial DNA may increase a person's risk of developing heart problems without affecting other parts of the body.

Other Names for This Gene

• MTTH
• tRNA histidine

Genomic Location

Normal Function

The MT-TL1 gene provides instructions for making a molecule called a transfer RNA (tRNA), which is a chemical cousin of DNA. Transfer RNAs help assemble protein building blocks (amino acids) into functioning proteins. The MT-TL1 gene provides instructions for making a specific form of tRNA that is designated as tRNALeu(UUR). During protein assembly, this molecule attaches to the amino acid leucine (Leu) and inserts it into the appropriate locations in the growing protein.

The tRNALeu(UUR) molecule is present in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Within mitochondria, tRNALeu(UUR) is involved in the assembly of proteins that carry out a series of chemical steps called oxidative phosphorylation. This process uses oxygen, simple sugars, and fatty acids to create adenosine triphosphate (ATP), the cell's main energy source.

In certain cells in the pancreas, called beta cells, mitochondria also play a role in controlling the amount of sugar (glucose) in the bloodstream. In response to high glucose levels, mitochondria help trigger the release of a hormone called insulin. Insulin regulates blood glucose levels by controlling how much glucose is passed from the blood into cells to be converted into energy.

Health Conditions Related to Genetic Changes

Maternally inherited diabetes and deafness

At least one mutation in the MT-TL1 gene causes maternally inherited diabetes and deafness (MIDD). People with this condition have diabetes and sometimes hearing loss, particularly of high tones. Less commonly, affected individuals have problems with their eyes, muscles, heart, or kidneys. The MT-TL1 gene mutation is the most common mutation in MIDD, involved in 85 percent of cases. It changes a single DNA building block (nucleotide) in the MT-TL1 gene; the nucleotide adenine is replaced by the nucleotide guanine at position 3243 in the gene (written as A3243G).

The A3243G mutation reduces the ability of tRNALeu(UUR) to add leucine to proteins that are being assembled, which slows protein production. Researchers believe that the A3243G mutation impairs the ability of mitochondria to help trigger insulin release. In people with MIDD, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how the A3243G mutation leads to hearing loss or the other features of MIDD.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Several mutations in the MT-TL1 gene have been identified in people with a condition called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This condition is characterized by recurrent severe headaches, muscle weakness (myopathy), hearing loss, stroke-like episodes including a loss of consciousness, seizures, and other problems affecting the nervous system. Most of these mutations change single nucleotides in the gene. The A3243G mutation (described above) is the most common mutation in MELAS. It is responsible for about 80 percent of all MELAS cases. This mutation impairs the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

Myoclonic epilepsy with ragged-red fibers

Mutations in the MT-TL1 gene have been found in a few people with features of myoclonic epilepsy with ragged-red fibers (MERRF). These individuals also have some features of MELAS (described above). This combination of signs and symptoms is called MERRF/MELAS overlap syndrome. The features of this syndrome include muscle twitches (myoclonus), muscle weakness (myopathy), difficulty coordinating movement (ataxia), hearing loss, seizures, and diabetes.

Mutations that cause MERRF/MELAS overlap syndrome each change single nucleotides in the MT-TL1 gene. Researchers have not determined how these genetic changes cause the signs and symptoms of MERRF/MELAS overlap syndrome.

Progressive external ophthalmoplegia

Mutations in the MT-TL1 gene are responsible for some cases of an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes drooping eyelids (ptosis).

Some cases of progressive external ophthalmoplegia result from the A3243G mutation, which is the same genetic change that typically causes MELAS and MIDD (described above). It is unclear how the same MT-TL1 gene mutation can result in different conditions. Researchers have not determined how changes in mtDNA lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition may be related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Mitochondrial complex I deficiency

MedlinePlus Genetics provides information about Mitochondrial complex I deficiency

Other disorders

About 20 mutations in the MT-TL1 gene have been reported, most of which change single nucleotides in the gene. These mutations are associated with a variety of signs and symptoms chiefly affecting the muscles and nervous system. People with MT-TL1 mutations often have muscle weakness, pain, and extreme fatigue, particularly during exercise (exercise intolerance). In some cases, the heart muscle is also weakened, which is known as cardiomyopathy. This abnormality prevents the heart from pumping normally.

A few children with changes in the MT-TL1 gene have experienced delayed development, psychiatric problems, or autism spectrum disorder (which affects communication and social interaction). MT-TL1 mutations also have been identified in a small number of cases of sudden infant death syndrome (SIDS), which is a major cause of death in children younger than 1 year.

Other Names for This Gene

• MTTL1
• tRNA leucine 1 (UUA/G)

Genomic Location

Normal Function

The MT-TV gene provides instructions for making a particular type of RNA, a molecule that is a chemical cousin of DNA. This type of RNA, called transfer RNA (tRNA), helps assemble protein building blocks known as amino acids into full-length, functioning proteins. The MT-TV gene provides instructions for a specific form of transfer RNA that is designated as tRNAVal. This molecule attaches to a particular amino acid, valine (Val), and inserts it into the appropriate locations in many different proteins.

The tRNAVal molecule is present only in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Through a process called oxidative phosphorylation, mitochondria use oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. The tRNAVal molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

Health Conditions Related to Genetic Changes

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Mutations in the MT-TV gene are a very rare cause of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Most cases of MELAS are caused by mutations in other mitochondrial genes, but a small number of cases resulting from mutations in the MT-TV gene have been reported. At least two mutations have been identified, each of which alters a single DNA building block (nucleotide) in the gene. One of these mutations replaces the nucleotide guanine with the nucleotide adenine at gene position 1642 (written as G1642A). Another mutation changes the nucleotide guanine to the nucleotide adenine at position 1644 (G1644A). Changes in the MT-TV gene may reduce the amount of tRNAVal available to assemble proteins within mitochondria. Because these proteins are needed for oxidative phosphorylation, MT-TV mutations may impair the ability of mitochondria to produce energy. Researchers have not determined how changes in mitochondrial energy production can lead to the specific features of MELAS.

Leigh syndrome

Changes in the MT-TV gene have been identified as a rare cause of Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. In a few cases, MT-TV mutations were found in people with signs and symptoms that did not appear until adulthood. Affected individuals 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.

Other disorders

A few other mutations in the MT-TV gene have been have been reported, most of which change single nucleotides in the gene. These mutations are responsible for a variety of signs and symptoms chiefly affecting the muscles and nervous system. Medical problems associated with MT-TV mutations have included recurrent migraine headaches, muscle weakness and problems with movement, poor coordination, seizures, hearing loss, learning disabilities, and loss of intellectual function (dementia). A heart condition called cardiomyopathy, which weakens and enlarges the heart muscle, also has been reported in a small number of affected individuals.

It is unclear why changes in the MT-TV gene can cause such a large variety of signs and symptoms. Even within a single family, affected individuals may have different health problems caused by the same genetic change.

Other Names for This Gene

• MTTV
• tRNA valine
• tRNA-Val, mitochondrial

Genomic Location

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.

In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.

The exact incidence of MELAS is unknown. It is one of the more common conditions in a group known as mitochondrial diseases. Together, mitochondrial diseases occur in about 1 in 4,000 people.