Maternally inherited diabetes and deafness (MIDD) is a form of diabetes that is often accompanied by hearing loss, especially of high tones. The diabetes in MIDD is characterized by high blood sugar (glucose) levels, known as hyperglycemia. This results from a shortage of the hormone insulin, which regulates the amount of glucose in the blood. In MIDD, the diabetes and hearing loss usually develop in mid-adulthood, although the age that they occur varies from childhood to late adulthood. Typically, hearing loss occurs before diabetes.

Some people with MIDD develop an eye disorder called macular retinal dystrophy, which is characterized by colored patches in the light-sensitive tissue that lines the back of the eye (the retina). This disorder does not usually cause vision problems in people with MIDD. Individuals with MIDD also may experience muscle cramps or weakness, particularly during exercise; heart problems; kidney disease; and constipation. Individuals with MIDD are often shorter than their peers.

Mutations in the MT-TL1, MT-TK, or MT-TE gene cause MIDD. These genes are found in mitochondrial DNA, which is part of cellular structures called mitochondria. Although most DNA is packaged in chromosomes within the cell nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA).

The MT-TL1, MT-TK, and MT-TE genes provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules 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. Similarly, the protein produced from the MT-TK gene, called tRNALys, attaches to the amino acid lysine (Lys) and inserts it into proteins being assembled. Also, the protein produced from the MT-TE gene, called tRNAGlu, attaches to the amino acid glutamic acid (Glu) and adds it to growing proteins.

These tRNA molecules are present only in mitochondria, and they help assemble proteins that are involved in producing energy for cells. In certain cells in the pancreas called beta cells, mitochondria also play a role in controlling the amount of glucose in the bloodstream. In response to high glucose levels, mitochondria help trigger the release of insulin, which stimulates cells to take up glucose from the blood.

Mutations in the MT-TL1, MT-TK, or MT-TE gene reduce the ability of tRNA to add amino acids to growing proteins, which slows protein production in mitochondria and impairs their functioning. Researchers believe that the disruption of mitochondrial function lessens the ability of mitochondria to help trigger insulin release. In people with this condition, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how the mutations lead to hearing loss or the other features of MIDD.

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-TK 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 full-length, functioning proteins. The MT-TK gene provides instructions for a specific form of tRNA that is designated as tRNALys. During protein assembly, this molecule attaches to a particular amino acid, lysine (Lys), and inserts it into the appropriate locations in the growing protein.

The tRNALys molecule is present in cellular compartments 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 tRNALys molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

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

A mutation in the MT-TK gene has been found in a small number of people with maternally inherited diabetes and deafness (MIDD), which is a condition characterized by diabetes and hearing loss, particularly of high tones. Less commonly, affected individuals have problems with their eyes, muscles, heart, or kidneys. The mutation involved in this condition changes a single DNA building block (nucleotide) in the MT-TK gene; the nucleotide adenine is replaced by the nucleotide guanine at gene position 8296 (written as A8296G). Researchers believe that the A8296G mutation impairs the ability of mitochondria to help trigger insulin release. In affected individuals, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how the A8296G mutation leads to hearing loss or the other features of MIDD.

Myoclonic epilepsy with ragged-red fibers

Several mutations in the MT-TK gene have been identified in people with myoclonic epilepsy with ragged-red fibers (MERRF). This condition is characterized by muscle twitches (myoclonus), recurrent seizures (epilepsy), abnormal muscle cells known as ragged-red fibers, and other problems with the nervous system. Most of the mutations involved in this condition change single nucleotides in the gene. One mutation causes about 80 percent of all MERRF cases. This genetic change replaces the nucleotide adenine with the nucleotide guanine at gene position 8344 (written as A8344G). The A8344G mutation impairs the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in the MT-TK gene lead to the specific signs and symptoms of MERRF. They continue to investigate the effects of mitochondrial gene mutations in various tissues, particularly in the brain.

A small number of people with a mutation in the MT-TK gene have some features of MERRF and some features of another mitochondrial disorder called mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These affected individuals are said to have MERRF/MELAS overlap syndrome. Additional signs and symptoms of this syndrome include recurrent severe headaches, muscle weakness (myopathy), difficulty coordinating movements (ataxia), hearing loss, and stroke-like episodes including a loss of consciousness. The mutation in the MT-TK gene that causes MERRF/MELAS overlap syndrome changes a single nucleotide in the gene. Specifically, it replaces the nucleotide thymine with the nucleotide cytosine at gene position 8356 (written as T8356C). It is unclear how this genetic change leads to the signs and symptoms of MERRF/MELAS overlap syndrome.

Leigh syndrome

The A8344G mutation, which is the most common mutation found in people with MERRF (described above), can also cause a progressive brain disorder called Leigh syndrome. Signs and symptoms of this condition usually begin during infancy or early childhood and include vomiting, seizures, delayed development, myopathy, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur in people with this disorder. Researchers have not determined why only some people with the A8344G mutation develop the signs and symptoms of Leigh syndrome.

Other disorders

A condition characterized by a weakened heart muscle (cardiomyopathy) and hearing loss is also caused by a mutation in the MT-TK gene. Affected individuals may also have myopathy and ataxia. This mutation (written as G8363A) replaces the nucleotide guanine with the nucleotide adenine at a certain location within the gene. It is unclear how this alteration in the MT-TK gene results in cardiomyopathy, hearing loss, and other symptoms.

Other Names for This Gene

• mitochondrial tRNA-Lys
• MTTK
• trnK

Genomic Location

The MT-TK gene is found on mitochondrial DNA.

Normal Function

The MT-TE 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-TE gene provides instructions for making a specific form of tRNA that is designated as tRNAGlu. During protein assembly, this molecule attaches to the amino acid glutamic acid (Glu) and inserts it into the appropriate locations in the growing protein.

The tRNAGlu molecule is present only in cellular compartments 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 tRNAGlu molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

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

A mutation in the MT-TE gene has been found in a small number of people with maternally inherited diabetes and deafness (MIDD). People with this condition have diabetes and sometimes hearing loss, particularly of high tones. Affected individuals may also have muscle weakness (myopathy) and problems with their eyes, heart, or kidneys. The mutation involved in this condition replaces the DNA building block (nucleotide) thymine with the nucleotide cytosine at position 14709 (written as T14709C). This mutation likely impairs the ability of mitochondria to help trigger insulin release. In affected individuals, diabetes results when the beta cells do not produce enough insulin to regulate blood glucose effectively. Researchers have not determined how the T14709C mutation leads to hearing loss or the other features of MIDD.

Other disorders

Mutations in the MT-TE gene are also involved in infantile transient mitochondrial myopathy (also known as benign COX deficiency myopathy). This rare condition occurs within the first few months of life and causes severe muscle weakness, poor muscle tone (hypotonia), and buildup of a chemical called lactic acid in the body (lactic acidosis). Affected infants often have difficulty feeding and need support from a machine to help them breathe. The signs and symptoms improve after several months, and most affected individuals show no symptoms of the condition by age 2 or 3.

The mutations involved in infantile transient mitochondrial myopathy change single nucleotides in mitochondrial DNA. Specifically, the nucleotide thymine at position 14674 is replaced by the nucleotide cytosine or guanine (written as T14674C or T14674G, respectively). These mutations impair oxidative phosphorylation. As a result, muscle cells cannot produce enough energy, leading to the muscle problems that affect infants with infantile transient mitochondrial myopathy. It is unknown why only muscles are involved or how affected infants recover from the condition.

Other Names for This Gene

• MTTE
• trnE

Genomic Location

MIDD 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.

Most of the body's cells contain thousands of mitochondria, each with one or more copies of mtDNA. These cells can have a mix of mitochondria containing mutated and unmutated DNA (heteroplasmy). The severity of MIDD is thought to be associated with the percentage of mitochondria with the mtDNA mutation.

About 1 percent of people with diabetes have MIDD. The condition is most common in the Japanese population and has been found in populations worldwide.