Metabolism is the process your body uses to make energy from the food you eat. Food is made up of proteins, carbohydrates, and fats. Chemicals in your digestive system (enzymes) break the food parts down into sugars and acids, your body's fuel. Your body can use this fuel right away, or it can store the energy in your body tissues. If you have a metabolic disorder, something goes wrong with this process.

Mitochondrial diseases are a group of metabolic disorders. Mitochondria are small structures that produce energy in almost all of your cells. They make it by combining oxygen with the fuel molecules (sugars and fats) that come from your food. When the mitochondria are defective, the cells do not have enough energy. The unused oxygen and fuel molecules build up in the cells and cause damage.

The symptoms of mitochondrial disease can vary. It depends on how many mitochondria are defective, and where they are in the body. Sometimes only one organ, tissue, or cell type is affected. But often the problem affects many of them. Muscle and nerve cells have especially high energy needs, so muscular and neurological problems are common. The diseases range from mild to severe. Some types can be fatal.

Genetic mutations cause these diseases. They usually happen before age 20, and some are more common in infants. There are no cures for these diseases, but treatments may help with symptoms and slow down the disease. They may include physical therapy, vitamins and supplements, special diets, and medicines.

Mitochondrial genetic disorders refer to a group of conditions that affect the mitochondria (the structures in each cell of the body that are responsible for making energy). People with these conditions can present at any age with almost any affected body system; however, the brain, muscles, heart, liver, nerves, eyes, ears and kidneys are the organs and tissues most commonly affected.

Symptom severity can also vary widely. Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy. Those caused by mutations in mitochondrial DNA are transmitted by maternal inheritance, while those caused by mutations in nuclear DNA may follow an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance. Treatment varies based on the specific type of condition and the signs and symptoms present in each person.

A champion swimmer, 16-year-old Joe Wise seems a healthy and happy high school junior. He enjoys time with friends, and he’s looking forward to college. But take a closer look, deep into his cells, and something’s not quite right. There’s a malfunction in the tiny capsule-shaped structures—called mitochondria —that power his cells. These abnormal mitochondria cause extreme fatigue and weakness in his legs, trouble breathing and a host of other problems.

“I used to play baseball, but now I can’t run so I can’t do that any more. Instead, I swim,” Joe says. In the past few years, he’s broken several national swimming records, and in 2008 he was on the U.S. Swim Team in the Beijing Paralympic games.

Joe is 1 of tens of thousands of people nationwide who have mitochondrial diseases, although estimates vary. There are dozens of subtypes, with each affecting less than 1 in 1,500 people. There’s no treatment or cure for any of these rare diseases.

Mitochondrial diseases are caused by abnormal genes that lead to flawed proteins or other molecules in the mitochondria. The various subtypes are caused by alterations in different genes, leading to worn-down cells in different parts of the body. Hardest hit are organs and tissues that need a lot of energy, like muscles, brain, heart, kidneys and liver. When the energy supply slumps, cells can become damaged or destroyed.

But mitochondria have importance beyond rare diseases. Even in healthy people, researchers have found, mitochondria can gradually deteriorate as we grow older. Malfunctioning mitochondria have been linked to diabetes, heart disease, Alzheimer’s disease, Parkinson’s disease and even normal aging. “If we can learn more about the rare mitochondrial disorders, the findings could have implications for understanding more common diseases,” says Dr. Vamsi Mootha of Harvard Medical School.

The rare mitochondrial diseases are notoriously difficult for doctors to recognize and diagnose. Depending on which cells are affected, people with mitochondrial diseases may have muscle weakness and pain, digestive problems, heart disease, seizures and many other symptoms. These diseases affect both children and adults. Some lead to early death. Because the symptoms vary widely, mitochondrial diseases are often mistaken for other conditions.

In Joe Wise’s case, he was an avid baseball and football player before age 8, when his father noticed he was walking and running a little funny. He felt tired and weak. He had trouble swallowing. Joe’s parents took him to see several specialists, who thought he might have juvenile arthritis, muscular dystrophy or maybe a problem with his hip. But eventually, a muscle biopsy showed that he had mitochondrial disease. His doctors didn’t expect him to live beyond age 14. “It was a real shock to the family,” Joe says. “It was something we suddenly had to learn a lot more about.”

Joe had to make difficult adjustments—watching his diet, being careful while walking and using a ventilator twice a day and overnight to help him breathe. He finds he feels weaker over time but continues to swim just about every day. “Swimming has helped in a lot of different ways,” Joe says. “It’s kept me out of a wheelchair. It’s kept me off a larger ventilator.” He’s now in training for the 2012 Paralympics.

Scientists don’t yet know why some patients like Joe can continue to exercise, while others have more severe disabilities. Over the last decades, though, researchers have learned a lot about mitochondria.

Each cell in the body contains dozens or even hundreds of mitochondria. Mitochondria produce about 90% of the energy that cells need to function. They differ from other cell components because each contains its own tiny loops of DNA, called mtDNA. The circular mtDNA differs from the well-known long DNA strands that make up the chromosomes contained in the control center, or nucleus, of your cells. Your nuclear DNA comes from both your mother and your father, but mtDNA comes only from your mother.

Scientists have learned that among the genes in mtDNA are instructions for making 13 proteins that mitochondria need to produce energy. Mutations in these genes can lead to dozens of different diseases.

But mitochondria contain much more than 13 proteins. They also contain over 1,000 proteins that come from genes in the cell’s nucleus. “We now know that the vast majority of genetic mitochondrial disorders are actually due to mutations in the nuclear genome ,” says Mootha.

These nuclear mutations are difficult to identify. While some research centers can now sequence the entire mtDNA and find the mutations that cause a patient’s disease, that can’t be done for most mutations in nuclear DNA.

Over the past 7 years, Mootha and his colleagues have been working to change that. They’ve used powerful new research tools to identify about 1,100 genes in our nuclear DNA that make proteins found in mitochondria. They’re now searching for mutations in these genes in patients who have mitochondrial disease. That will help with developing diagnostics, he says. “And once we know the molecular underpinnings of these disorders, they may offer clues for completely new treatment strategies.”

Several potential therapies for mitochondrial diseases are already being explored. Some patients with mtDNA mutations have a mix of normal and mutant mtDNA in their cells. Researchers are searching for ways to shift the balance toward more normal DNA. At the University of Texas Southwestern Medical School, Dr. Ronald Haller is testing to see if endurance training can safely encourage this shift, or at least improve physical health, in patients with mtDNA mutations.

“The benefits of exercise training in healthy people are well-recognized,” Haller says. One benefit is to increase the number of mitochondria in your muscles. “We want to see if some of these same benefits extend to patients with mitochondrial disease.”

Haller and his colleagues have already conducted small studies that suggest patients who train can improve their ability to walk and do other daily activities. He’s also found evidence that mitochondrial numbers shrink once patients stop training—which also happens in healthy people. Haller has now begun a larger study of 40 patients to see how exercise training, and taking a break from exercise, affect mitochondria and exercise capacity.

“A lot of exciting new research in mitochondrial biology is taking place right now,” says Mootha. “As we learn more about these disorders, we’ll hopefully be able to convert this knowledge into better therapies.”

Mitochondrial Disease Symptoms

Mitochondrial disease can affect different parts of the body. Symptoms can range from mild to severe and might include:

• Poor growth
• Muscle weakness or fatigue
• Visual or hearing problems
• Mental retardation
• Heart, liver or kidney disease
• Digestive problems
• Breathing difficulties
• Diabetes
• Seizures

Q: What are mitochondrial diseases or disorders?

A: Mitochondria are tiny parts of almost every cell in your body. Mitochondria are like the power house of the cells. They turn sugar and oxygen into energy that the cells need to work.

In mitochondrial diseases, the mitochondria cannot efficiently turn sugar and oxygen into energy, so the cells do not work correctly.

There are many types of mitochondrial disease, and they can affect different parts of the body: the brain, kidneys, muscles, heart, eyes, ears, and others. Mitochondrial diseases can affect one part of the body or can affect many parts. They can affect those part(s) mildly or very seriously.

Not everyone with a mitochondrial disease will show symptoms. However, when discussing the group of mitochondrial diseases that tend to affect children, symptoms usually appear in the toddler and preschool years.

Mitochondrial diseases and disorders are the same thing.

Q: Is there a relationship between mitochondrial disease and autism?

A: A child with a mitochondrial disease:

• may also have an autism spectrum disorder,
• may have some of the symptoms/signs of autism, or
• may not have any signs or symptoms related to autism.

A child with autism may or may not have a mitochondrial disease. When a child has both autism and a mitochondrial disease, they sometimes have other problems as well, including epilepsy, problems with muscle tone, and/or movement disorders.

More research is needed to find out how common it is for people to have autism and a mitochondrial disorder. Right now, it seems rare. In general, more research about mitochondrial disease and autism is needed.

Q: What is regressive encephalopathy?

A: Encephalopathy is a medical term for a disease or disorder of the brain. It usually means a slowing down of brain function.

Regression happens when a person loses skills that they used to have like walking or talking or even being social.

Regressive encephalopathy means there is a disease or disorder in the brain that makes a person lose skills they once had.

We know that sometimes children with mitochondrial diseases seem to be developing as they should, but around toddler or preschool age, they regress. The disease was there all the time, but something happens that “sets it off”. This could be something like malnutrition, an illness such as flu, a high fever, dehydration, or it could be something else.

Q: Is there a relationship between autism and encephalopathy?

A: Most children with an autism spectrum disorder do not and have not had an encephalopathy. Some children with an autism spectrum disorder have had regression and some have had a regressive encephalopathy.

Q: What do we know about the relationship between mitochondrial disease and other disorders related to the brain?

A: Different parts of the brain have different functions. The area of the brain that is damaged by a mitochondrial disease determines how the person is impacted. This means that a person could have seizures; trouble talking or interacting with people; difficulty eating; muscle weakness, or other problems. They could have one issue or several.

Q: Do vaccines cause or worsen mitochondrial diseases?

A: As of now, there are no scientific studies that say vaccines cause or worsen mitochondrial diseases. We do know that certain illnesses that can be prevented by vaccines, such as the flu, can trigger the regression that is related to a mitochondrial disease. More research is needed to determine if there are rare cases where underlying mitochondrial disorders are triggered by anything related to vaccines. However, we know that for most children, vaccines are a safe and important way to prevent them from getting life-threatening diseases.

Q: Are all children routinely tested for mitochondrial diseases? What about children with autism?

A: Children are not routinely tested for mitochondrial diseases. This includes children with autism and other developmental delays.

Testing is not easy and may involve getting multiple samples of blood, and often samples of muscle. Doctors decide whether testing for mitochondrial diseases should be done based on a child’s signs and symptoms.

Q: Should I have my child tested for a mitochondrial disease?

A: If you are worried that your child might have a mitochondrial disease, talk to your child’s doctor.

The following conditions are associated with changes in the structure of mitochondrial DNA.

Age-related hearing loss

Changes in mitochondrial DNA are among the best-studied genetic factors associated with age-related hearing loss. This form of hearing loss develops with age and can begin as early as a person's thirties or forties. It typically affects both ears and worsens gradually over time, making it difficult to understand speech and hear other sounds. This condition results from a combination of genetic, environmental, and lifestyle factors, many of which have not been identified.

As people age, mitochondrial DNA accumulates damaging mutations, including deletions and other changes. This damage results from a buildup of harmful molecules called reactive oxygen species, which are byproducts of energy production in mitochondria. Mitochondrial DNA is especially vulnerable because it has a limited ability to repair itself. As a result, reactive oxygen species easily damage mitochondrial DNA, causing cells to malfunction and ultimately to die. Cells that have high energy demands, such as those in the inner ear that are critical for hearing, are particularly sensitive to the effects of mitochondrial DNA damage. This damage can irreversibly alter the function of the inner ear, leading to hearing loss.

Cancers

Mitochondrial DNA is prone to somatic mutations, which are a type of noninherited mutation. Somatic mutations occur in the DNA of certain cells during a person's lifetime and typically are not passed to future generations. There is limited evidence linking somatic mutations in mitochondrial DNA with certain cancers, including breast, colon, stomach, liver, and kidney tumors. These mutations might also be associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma).

It is possible that somatic mutations in mitochondrial DNA increase the production of reactive oxygen species. These molecules damage mitochondrial DNA, causing a buildup of additional somatic mutations. Researchers are investigating how these mutations could be related to uncontrolled cell division and the growth of cancerous tumors.

Cyclic vomiting syndrome

Some cases of cyclic vomiting syndrome, particularly those that begin in childhood, may be related to changes in mitochondrial DNA. This disorder causes recurrent episodes of nausea, vomiting, and tiredness (lethargy). Some of the genetic changes alter single DNA building blocks (nucleotides), whereas others rearrange larger segments of mitochondrial DNA. These changes likely impair the ability of mitochondria to produce energy. Researchers speculate that the impaired mitochondria may affect certain cells of the autonomic nervous system, which is the part of the nervous system that controls involuntary body functions such as heart rate, blood pressure, and digestion. However, it remains unclear how these changes could cause the recurrent episodes characteristic of cyclic vomiting syndrome.

Cytochrome c oxidase deficiency

Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency, which is a condition that can affect several parts of the body, including the muscles used for movement (skeletal muscles), the heart, the brain, or the liver.

The mitochondrial genes associated with cytochrome c oxidase deficiency provide instructions for making proteins that are part of a large enzyme group (complex) called cytochrome c oxidase (also known as complex IV). Cytochrome c oxidase is responsible for the last step in oxidative phosphorylation before the generation of ATP. The mtDNA mutations that cause this condition alter the proteins that make up cytochrome c oxidase. As a result, cytochrome c oxidase cannot function. A lack of functional cytochrome c oxidase disrupts oxidative phosphorylation, causing a decrease in ATP production. Researchers believe that impaired oxidative phosphorylation can lead to cell death in tissues that require large amounts of energy, such as the brain, muscles, and heart. Cell death in these and other sensitive tissues likely contribute to the features of cytochrome c oxidase deficiency.

Kearns-Sayre syndrome

Most people with Kearns-Sayre syndrome have a single, large deletion of mitochondrial DNA. The deletions range from 1,000 to 10,000 nucleotides, and the most common deletion is 4,997 nucleotides. Kearns-Sayre syndrome primarily affects the eyes, causing weakness of the eye muscles (ophthalmoplegia) and breakdown of the light-sensing tissue at the back of the eye (retinopathy). The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation, causing a decrease in cellular energy production. Researchers have not determined how these deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy.

Leber hereditary optic neuropathy

Mutations in four mitochondrial genes, MT-ND1, MT-ND4, MT-ND4L, and MT-ND6, have been identified in people with Leber hereditary optic neuropathy. These genes provide instructions for making proteins that are part of a large enzyme complex. This enzyme, known as complex I, is necessary for oxidative phosphorylation. The mutations responsible for Leber hereditary optic neuropathy change single amino acids in these proteins, which may affect the generation of ATP within mitochondria. However, it remains unclear 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 vision loss and the other medical problems associated with Leber hereditary optic neuropathy.

Leigh syndrome

Mutations in one of several different mitochondrial genes can cause Leigh syndrome, which is a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.

Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation. For example, the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6, provides instructions for a protein that makes up one part of complex V, an important enzyme in oxidative phosphorylation that generates ATP in the mitochondria. The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. Many of these proteins play an important role in oxidative phosphorylation. The mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation. Although the mechanism is unclear, it is thought that impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome.

Maternally inherited diabetes and deafness

Mutations in at least three mitochondrial genes, MT-TL1, MT-TK, and MT-TE, can cause mitochondrial diabetes and deafness (MIDD). People with this condition have diabetes and sometimes hearing loss, particularly of high tones. The MT-TL1, MT-TK, and MT-TE genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. In certain cells in the pancreas (beta cells), mitochondria help monitor blood sugar levels. In response to high levels of sugar, mitochondria help trigger the release of a hormone called insulin, which controls blood sugar levels. The MT-TL1, MT-TK, and MT-TE gene mutations associated with MIDD slow protein production in mitochondria and impair their function. Researchers believe that the disruption of mitochondrial function lessens the mitochondria's ability to help trigger insulin release. In people with MIDD, diabetes results when the beta cells do not produce enough insulin to regulate blood sugar effectively. Researchers have not determined how mutations in these genes lead to hearing loss.

Mitochondrial complex III deficiency

Mutations in the MT-CYB gene found in mitochondrial DNA can cause mitochondrial complex III deficiency. When caused by mutations in this gene, the condition is usually characterized by muscle weakness (myopathy) and pain, especially during exercise (exercise intolerance). More severely affected individuals may have problems with other body systems, including the liver, kidneys, heart, and brain.

The MT-CYB gene provides instructions for making a protein called cytochrome b. This protein is one component of complex III, one of several complexes that carry out oxidative phosphorylation. Most MT-CYB gene mutations involved in mitochondrial complex III deficiency change single amino acids in the cytochrome b protein or lead to an abnormally short protein. These cytochrome b alterations impair the formation of complex III, severely reducing the complex's activity and oxidative phosphorylation. Damage to the skeletal muscles or other tissues and organs caused by the lack of cellular energy leads to the features of mitochondrial complex III deficiency.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Mutations in at least five mitochondrial genes, MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV, can cause the characteristic features of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Some of these genes provide instructions for making proteins that are part of a large enzyme complex, called complex I, that is necessary for oxidative phosphorylation. The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.

One particular mutation in the MT-TL1 gene causes more than 80 percent of all cases of MELAS. This mutation, written as A3243G, replaces the nucleotide adenine with the nucleotide guanine at position 3243 in the MT-TL1 gene.

The mutations that cause MELAS impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA 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 at least four mitochondrial genes, MT-TK, MT-TL1, MT-TH, and MT-TS1, can cause the signs and symptoms of myoclonic epilepsy with ragged-red fibers (MERRF). These genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria.

One particular mutation in the MT-TK gene causes more than 80 percent of all cases of MERRF. This mutation, written as A8344G, replaces the nucleotide adenine with the nucleotide guanine at position 8344 in the MT-TK gene.

Mutations in the MT-TK, MT-TL1, MT-TH, and MT-TS1 genes impair the ability of mitochondria to make proteins, use oxygen, and produce energy. It remains unclear how mutations in these genes lead to the muscle problems and neurological features of MERRF.

Neuropathy, ataxia, and retinitis pigmentosa

Mutations in one mitochondrial gene, MT-ATP6, have been found in people with neuropathy, ataxia, and retinitis pigmentosa (NARP). The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. This protein forms one part (subunit) of an enzyme called ATP synthase. This enzyme, which is also known as complex V, is responsible for the last step of oxidative phosphorylation, in which a molecule called adenosine diphosphate (ADP) is converted to ATP. Mutations in the MT-ATP6 gene alter the structure or function of ATP synthase, reducing the ability of mitochondria to make ATP. It is unclear how this disruption in mitochondrial energy production leads to muscle weakness, vision loss, and the other specific features of NARP.

Nonsyndromic hearing loss

Mutations in mitochondrial DNA are associated with nonsyndromic hearing loss, which is loss of hearing that is not associated with other signs and symptoms. These mutations can occur in at least two mitochondrial genes: MT-RNR1 and MT-TS1.

The MT-RNR1 gene provides instructions for making a type of ribosomal RNA called 12S RNA. This molecule helps assemble protein building blocks known as amino acids into functioning proteins that carry out oxidative phosphorylation within mitochondria. Mutations in this gene increase the risk of hearing loss, particularly in people who take prescription antibiotic medications called aminoglycosides. These antibiotics are typically used to treat life-threatening and chronic bacterial infections such as tuberculosis. Aminoglycosides kill bacteria by binding to their ribosomal RNA and disrupting the bacteria's ability to make proteins. Common genetic changes in the MT-RNR1 gene can make the 12S RNA in human cells look similar to bacterial ribosomal RNA. As a result, aminoglycosides can target the altered 12S RNA just as they target bacterial ribosomal RNA. The antibiotic easily binds to the abnormal 12S RNA, which impairs the ability of mitochondria to produce proteins needed for oxidative phosphorylation. Researchers believe that this unintended effect of aminoglycosides may reduce the amount of ATP produced in mitochondria, increase the production of harmful byproducts, and eventually cause the cell to self-destruct (undergo apoptosis).

The MT-TS1 gene provides instructions for making a form of tRNA designated as tRNASer. This molecule helps assemble amino acids into full-length, functioning proteins. Most MT-TS1 gene mutations likely disrupt the normal production of the tRNASer molecule or alter its structure. As a result, less tRNASer is available to assemble proteins within mitochondria. These changes reduce the production of proteins needed for oxidative phosphorylation, which may impair the ability of mitochondria to make ATP.

Researchers have not determined why the effects of mutations in these genes are usually limited to cells in the inner ear that are essential for hearing. Other genetic or environmental factors likely play a role in the signs and symptoms associated with these mutations.

Pearson marrow-pancreas syndrome

As in Kearns-Sayre syndrome (described above), deletion of mitochondrial DNA causes Pearson marrow-pancreas syndrome. This severe condition affects the development of blood cells and the function of the pancreas and other organs; it is often fatal in infancy or early childhood. The size and location of mitochondrial DNA deletions vary, usually ranging from 1,000 to 10,000 nucleotides. About 20 percent of affected individuals have a deletion of 4,997 nucleotides; this genetic change is also common in Kearns-Sayre syndrome. Loss of mitochondrial DNA impairs oxidative phosphorylation, which reduces the energy available to cells. However, it is unknown how mitochondrial DNA deletions lead to the specific signs and symptoms of Pearson marrow-pancreas syndrome.

It is not clear why the same deletion can result in different signs and symptoms. Researchers suggest that the tissues in which the mitochondrial DNA deletions are found determine which features develop. Some individuals with Pearson marrow-pancreas syndrome who survive past early childhood develop signs and symptoms of Kearns-Sayre syndrome later in life.

Progressive external ophthalmoplegia

Mitochondrial DNA deletion or mutation can be involved in an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis). Some people with progressive external ophthalmoplegia have a single large deletion of mitochondrial DNA. The most common deletion is 4,997 nucleotides, as in Kearns-Sayre syndrome (described above). Other people with the condition have a mutation in the mitochondrial gene MT-TL1. This gene provides instructions for making a specific tRNA called tRNA. This tRNA is found only in mitochondria and is important in assembling the proteins that carry out oxidative phosphorylation.

The A3243G mutation (described above), which is the same genetic change that has been associated with MELAS, is a relatively common cause of progressive external ophthalmoplegia. It is unclear how the same MT-TL1 gene mutation can result in different signs and symptoms. Mutations in the MT-TL1 gene impair the ability of mitochondria to make proteins, use oxygen, and produce energy, although researchers have not determined how these mutations lead to the specific signs and symptoms of progressive external ophthalmoplegia.

Other disorders

Inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body's systems. These mutations disrupt the mitochondria's ability to generate energy for the cell efficiently. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues with high energy requirements (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, some frequently observed features include muscle weakness and wasting, movement problems, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

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

A buildup of somatic mutations in mitochondrial DNA has been associated with an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person's lifetime may play a role in the normal aging process.

Age-related hearing loss (also called presbycusis, pronounced prez-buh-KYOO-sis) is hearing loss that occurs gradually for many of us as we grow older. It is one of the most common conditions affecting adults as we age. Approximately 15% of American adults (37.5 million) ages 18 and over report some trouble hearing, and about one in three people in the U.S. between the ages of 65 and 74 has hearing loss. Nearly half of those older than 75 have difficulty hearing.

Having trouble hearing can make it hard to understand and follow a doctor's advice, respond to warnings, and hear phones, doorbells, and smoke alarms. Hearing loss can also make it hard to enjoy talking with family and friends, leading to feelings of isolation.

Hearing loss typically occurs in both ears as we age. Because the loss is gradual, you may not realize that you've lost some of your ability to hear.

Cancer begins in your cells, which are the building blocks of your body. Normally, your body forms new cells as you need them, replacing old cells that die. Sometimes this process goes wrong. New cells grow even when you don't need them, and old cells don't die when they should. These extra cells can form a mass called a tumor. Tumors can be benign or malignant. Benign tumors aren't cancer while malignant ones are. Cells from malignant tumors can invade nearby tissues. They can also break away and spread to other parts of the body.

Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for where they start. For example, lung cancer starts in the lung, and breast cancer starts in the breast. The spread of cancer from one part of the body to another is called metastasis. Symptoms and treatment depend on the cancer type and how advanced it is. Most treatment plans may include surgery, radiation and/or chemotherapy. Some may involve hormone therapy, immunotherapy or other types of biologic therapy, or stem cell transplantation.

Progressive external ophthalmoplegia is a condition characterized by weakness of the eye muscles. The condition typically appears in adults between ages 18 and 40 and slowly worsens over time. The first sign of progressive external ophthalmoplegia is typically drooping eyelids (ptosis), which can affect one or both eyelids. As ptosis worsens, affected individuals may use the forehead muscles to try to lift the eyelids, or they may lift up their chin in order to see. Another characteristic feature of progressive external ophthalmoplegia is weakness or paralysis of the muscles that move the eye (ophthalmoplegia). Affected individuals have to turn their head to see in different directions, especially as the ophthalmoplegia worsens. People with progressive external ophthalmoplegia may also have general weakness of the muscles used for movement (myopathy), particularly those in the neck, arms, or legs. The weakness may be especially noticeable during exercise (exercise intolerance). Muscle weakness may also cause difficulty swallowing (dysphagia).

When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells contain an excess of cell structures called mitochondria and are known as ragged-red fibers.

Although muscle weakness is the primary symptom of progressive external ophthalmoplegia, this condition can be accompanied by other signs and symptoms. In these instances, the condition is referred to as progressive external ophthalmoplegia plus (PEO+). Additional signs and symptoms can include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), weakness and loss of sensation in the limbs due to nerve damage (neuropathy), impaired muscle coordination (ataxia), a pattern of movement abnormalities known as parkinsonism, and depression.

Progressive external ophthalmoplegia is part of a spectrum of disorders with overlapping signs and symptoms. Similar disorders include ataxia neuropathy spectrum and Kearns-Sayre syndrome. Like progressive external ophthalmoplegia, the other conditions in this spectrum can involve weakness of the eye muscles. However, these conditions have many additional features not shared by most people with progressive external ophthalmoplegia.

Pearson syndrome is a severe disorder that usually begins in infancy. It causes problems with the development of blood-forming (hematopoietic) cells in the bone marrow that have the potential to develop into different types of blood cells. For this reason, Pearson syndrome is considered a bone marrow failure disorder. Function of the pancreas and other organs can also be affected.

Most affected individuals have a shortage of red blood cells (anemia), which can cause pale skin (pallor), weakness, and fatigue. Some of these individuals also have low numbers of white blood cells (neutropenia) and platelets (thrombocytopenia). Neutropenia can lead to frequent infections; thrombocytopenia sometimes causes easy bruising and bleeding. When visualized under the microscope, bone marrow cells from affected individuals may appear abnormal. Often, early blood cells (hematopoietic precursors) have multiple fluid-filled pockets called vacuoles. In addition, red blood cells in the bone marrow can have an abnormal buildup of iron that appears as a ring of blue staining in the cell after treatment with certain dyes. These abnormal cells are called ring sideroblasts.

In people with Pearson syndrome, the pancreas does not work as well as usual. The pancreas produces and releases enzymes that aid in the digestion of fats and proteins. Reduced function of this organ can lead to high levels of fats in the liver (liver steatosis). The pancreas also releases insulin, which helps maintain correct levels of blood glucose, also called blood sugar. A small number of individuals with Pearson syndrome develop diabetes, a condition characterized by abnormally high blood glucose levels that can be caused by a shortage of insulin. In addition, affected individuals may have scarring (fibrosis) in the pancreas.

People with Pearson syndrome have a reduced ability to absorb nutrients from the diet (malabsorption), and most affected infants have an inability to grow and gain weight at the expected rate (failure to thrive). Another common occurrence in people with this condition is buildup in the body of a chemical called lactic acid (lactic acidosis), which can be life-threatening. In addition, liver and kidney problems can develop in people with this condition. Some people with Pearson syndrome have droopy eyelids (ptosis), vision problems, hearing loss, seizures, or movement disorders.

About half of children with this severe disorder die in infancy or early childhood due to severe lactic acidosis or liver failure. Many of those who survive develop signs and symptoms later in life of a related disorder called Kearns-Sayre syndrome. This condition causes weakness of muscles around the eyes and other problems.

Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. In contrast, syndromic hearing loss occurs with signs and symptoms affecting other parts of the body.

Nonsyndromic hearing loss can be classified in several different ways. One common way is by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). Each of these types of hearing loss includes multiple subtypes. DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. For example, DFNA1 was the first type of autosomal dominant nonsyndromic hearing loss to be identified.

The characteristics of nonsyndromic hearing loss vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones.

Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear. The inner ear processes sound and sends the information to the brain in the form of electrical nerve impulses. Less commonly, nonsyndromic hearing loss is described as conductive, meaning it results from changes in the middle ear. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic hearing loss, particularly a type called DFNX2, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss.

Depending on the type, nonsyndromic hearing loss can become apparent at any time from infancy to old age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.

Neuropathy, ataxia, and retinitis pigmentosa (NARP) is a condition that causes a variety of signs and symptoms that mainly affect the nervous system. The condition typically begins in childhood or early adulthood, and the signs and symptoms usually worsen over time. Most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye (the retina). In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.

Learning disabilities and developmental delays are often seen in children with NARP, and older individuals with this condition may experience a loss of intellectual function (dementia). Other features of NARP include seizures, hearing loss, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). These signs and symptoms vary among affected individuals.

Myoclonic epilepsy with ragged-red fibers (MERRF) is a disorder that affects many parts of the body, particularly the muscles and nervous system. In most cases, the signs and symptoms of this disorder appear during childhood or adolescence. The features of MERRF vary widely among affected individuals, even among members of the same family.

MERRF is characterized by muscle twitches (myoclonus), weakness (myopathy), and progressive stiffness (spasticity). When the muscle cells of affected individuals are stained and viewed under a microscope, these cells usually appear abnormal. These abnormal muscle cells are called ragged-red fibers. Other features of MERRF include recurrent seizures (epilepsy), difficulty coordinating movements (ataxia), a loss of sensation in the extremities (peripheral neuropathy), and slow deterioration of intellectual function (dementia). People with this condition may also develop hearing loss or optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain. Affected individuals sometimes have short stature and a form of heart disease known as cardiomyopathy. Less commonly, people with MERRF develop fatty tumors, called lipomas, just under the surface of the skin.

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.

Mitochondrial complex III deficiency is one of several conditions caused by dysfunction of mitochondria, which are specialized compartments in cells that generate more than 90% of the energy required by the body. It is a severe, multisystem disorder that includes features such as lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Involvement of internal organs, including liver disease and renal tubulopathy, may also occur. Symptoms typically begin at birth. Many affected individuals die in early childhood, but some have survived longer.

It is generally caused by mutations in nuclear DNA in the BCS1L, UQCRB and UQCRQ genes and inherited in an autosomal recessive manner. However, it may also be caused by mutations in mitochondrial DNA in the MTCYB gene, which is passed down maternally or occurs sporadically and may result in a milder form of the condition.

Treatment generally focuses on alleviating symptoms and/or slowing down the progression of the disease, and effectiveness can vary among individuals.

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.

Leigh syndrome is a rare inherited neurometabolic disorder that affects the central nervous system. This disorder begins in infants between the ages of 3 months and 2 years. Rarely, it can occur in teenagers and adults.

Symptoms of Leigh syndrome usually progress rapidly, and may include:

• Poor sucking ability
• Loss of head control and motor skills
• Loss of appetite
• Vomiting
• Irritability
• Continuous crying
• Seizures

 As the disorder progresses, symptoms may also include:

• Generalized weakness
• Lack of muscle tone
• Episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function

Leigh syndrome can be caused by mutations in mitochondrial DNA or by deficiencies of an enzyme called pyruvate dehydrogenase.

Genetic mutations in mitochondrial DNA interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements. These genetic mutations result in a chronic lack of energy in the cells which affects the central nervous system and causes progressive degeneration of motor functions.

There is also a form of Leigh syndrome (X-linked recessive inheritance) that is the result of mutations in a gene that produces another group of substances important for cell metabolism. This gene is only found on the X chromosome. 

The most common treatment for Leigh syndrome is thiamine or Vitamin B1. Oral sodium bicarbonate or sodium citrate may be prescribed to manage lactic acidosis. Researchers are testing dichloroacetate to establish its effectiveness in treating lactic acidosis. In individuals with the X-linked form of Leigh syndrome, a high-fat, low-carbohydrate diet may be recommended.

Leber hereditary optic neuropathy (LHON) is an inherited form of vision loss. Although this condition usually begins in a person's teens or twenties, rare cases may appear in early childhood or later in adulthood. For unknown reasons, males are affected much more often than females.

Blurring and clouding of vision are usually the first symptoms of LHON. These vision problems may begin in one eye or simultaneously in both eyes; if vision loss starts in one eye, the other eye is usually affected within several weeks or months. Over time, vision in both eyes worsens with a severe loss of sharpness (visual acuity) and color vision. This condition mainly affects central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Vision loss results from the death of cells in the nerve that relays visual information from the eyes to the brain (the optic nerve). Although central vision gradually improves in a small percentage of cases, in most cases the vision loss is profound and permanent.

Vision loss is typically the only symptom of LHON; however, some families with additional signs and symptoms have been reported. In these individuals, the condition is described as "LHON plus." In addition to vision loss, the features of LHON plus can include movement disorders, tremors, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). Some affected individuals develop features similar to multiple sclerosis, which is a chronic disorder characterized by muscle weakness, poor coordination, numbness, and a variety of other health problems.

Kearns-Sayre syndrome (KSS) is a neuromuscular disorder defined by the triad of onset before age 20 years, pigmentary retinopathy (a "salt-and-pepper" pigmentation in the retina that can affect vision, but often leaves it intact), and progressive external ophthalmoplegia (PEO). In addition, affected individuals have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Kearns-Sayre syndrome is a mitochondrial DNA (mtDNA) deletion syndrome. It results from abnormalities in the DNA of mitochondria - small rod-like structures found in every cell of the body that produce the energy that drives cellular functions. This and other mitochondrial diseases correlate with specific DNA mutations that cause problems with many of the organs and tissues in the body, resulting in multisystem effects. Treatment for this slowly progressive disorder is generally symptomatic and supportive.

Cytochrome c oxidase deficiency is a genetic condition that can affect several parts of the body, including the muscles used for movement (skeletal muscles), the heart, the brain, or the liver. Signs and symptoms of cytochrome c oxidase deficiency usually begin before age 2 but can appear later in mildly affected individuals.

The severity of cytochrome c oxidase deficiency varies widely among affected individuals, even among those in the same family. People who are mildly affected tend to have muscle weakness (myopathy) and poor muscle tone (hypotonia) with no other related health problems. More severely affected people have problems in multiple body systems, often including severe brain dysfunction (encephalomyopathy). Approximately one-quarter of individuals with cytochrome c oxidase deficiency have a type of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). Another possible feature of this condition is an enlarged liver (hepatomegaly), which may lead to liver failure. Most individuals with cytochrome c oxidase deficiency have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can cause nausea and an irregular heart rate, and can be life-threatening.

Many people with cytochrome c oxidase deficiency have a specific group of features known as Leigh syndrome. The signs and symptoms of Leigh syndrome include loss of mental function, movement problems, hypertrophic cardiomyopathy, eating difficulties, and brain abnormalities. Cytochrome c oxidase deficiency is one of the many causes of Leigh syndrome.

Many individuals with cytochrome c oxidase deficiency do not survive past childhood, although some individuals with mild signs and symptoms live into adolescence or adulthood.

Cyclic vomiting syndrome is a disorder that causes recurrent episodes of nausea, vomiting, and tiredness (lethargy). This condition is diagnosed most often in young children, but it can affect people of any age.

The episodes of nausea, vomiting, and lethargy last anywhere from an hour to 10 days. An affected person may vomit several times per hour, potentially leading to a dangerous loss of fluids (dehydration). Additional symptoms can include unusually pale skin (pallor), abdominal pain, diarrhea, headache, fever, and an increased sensitivity to light (photophobia) or to sound (phonophobia). In most affected people, the signs and symptoms of each attack are quite similar. These attacks can be debilitating, making it difficult for an affected person to go to work or school.

Episodes of nausea, vomiting, and lethargy can occur regularly or apparently at random, or can be triggered by a variety of factors. The most common triggers are emotional excitement and infections. Other triggers can include periods without eating (fasting), temperature extremes, lack of sleep, overexertion, allergies, ingesting certain foods or alcohol, and menstruation.

If the condition is not treated, episodes usually occur four to 12 times per year. Between attacks, vomiting is absent, and nausea is either absent or much reduced. However, many affected people experience other symptoms during and between episodes, including pain, lethargy, digestive disorders such as gastroesophageal reflux and irritable bowel syndrome, and fainting spells (syncope). People with cyclic vomiting syndrome are also more likely than people without the disorder to experience depression, anxiety, and panic disorder. It is unclear whether these health conditions are directly related to nausea and vomiting.

Cyclic vomiting syndrome is often considered to be a variant of migraines, which are severe headaches often associated with pain, nausea, vomiting, and extreme sensitivity to light and sound. Cyclic vomiting syndrome is likely the same as or closely related to a condition called abdominal migraine, which is characterized by attacks of stomach pain and cramping. Attacks of nausea, vomiting, or abdominal pain in childhood may be replaced by migraine headaches as an affected person gets older. Many people with cyclic vomiting syndrome or abdominal migraine have a family history of migraines.

Most people with cyclic vomiting syndrome have normal intelligence, although some affected people have developmental delay or intellectual disability. Autism spectrum disorder, which affects communication and social interaction, have also been associated with cyclic vomiting syndrome. Additionally, muscle weakness (myopathy) and seizures are possible. People with any of these additional features are said to have cyclic vomiting syndrome plus.

People with mitochondrial genetic disorders can present at any age with almost any affected body system. While some conditions may only affect a single organ, many involve multiple organ systems including the brain, muscles, heart, liver, nerves, eyes, ears and/or kidneys. Symptom severity can also vary widely. The most common signs and symptoms include:

• Poor growth
• Loss of muscle coordination
• Muscle weakness
• Seizures
• Autism
• Problems with vision and/or hearing
• Developmental delay
• Learning disabilities
• Heart, liver, and/or kidney disease
• Gastrointestinal disorders
• Diabetes
• Increased risk of infection
• Thyroid and/or adrenal abnormalities
• Autonomic dysfunction
• Dementia

Unfortunately, mitochondrial genetic disorders can be difficult to diagnose, and many affected people may never receive a specific diagnosis. They are often suspected in people who have a condition that effects multiple, unrelated systems of the body. In some cases, the pattern of symptoms may be suggestive of a specific mitochondrial condition. If the disease-causing gene(s) associated with the particular condition is known, the diagnosis can then be confirmed with genetic testing.

If a mitochondrial genetic disorder is suspected but the signs and symptoms do not suggest a specific diagnosis, a more extensive work-up may be required. In these cases, a physician may start by evaluating the levels of certain substances in a sample of blood or cerebrospinal fluid. Other tests that can support a diagnosis include:

• Exercise testing
• Magnetic resonance spectroscopy (detects abnormalities in the brain's chemical makeup)
• Imaging studies of the brain such as MRI or CT scan
• Electroencephalography (EEG)
• Tests that evaluate the heart including electrocardiography and echocardiography
• Muscle biopsy

When possible, confirming a diagnosis with genetic testing can have important implications for family members. Identifying the disease-causing gene(s) will give the family information about the inheritance pattern and the risk to other family members. It will also allow other at-risk family members to undergo genetic testing.