U.S. DEPARTMENT OF HEALTH

AND HUMAN SERVICES

National Institutes of Health

Mitochondrial 

Myopathies

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Mitochondrial Myopathies

What are mitochondrial myopathies?

Mitochondrial diseases are caused by defects in mitochondria, which are 

energy factories found inside almost all the 

cells in the body. Mitochondrial diseases that 

cause prominent muscular problems are called 

mitochondrial myopathies (myo means muscle 

and pathos means disease), while mitochondrial 

diseases that causes both prominent muscular 

and neurological problems are called 

mitochondrial encephalomyopathies 

(encephalo refers to the brain).

A typical human cell relies on hundreds of 

mitochondria to meet its energy needs. The 

symptoms of mitochondrial disease vary, 

because a person can have a unique mixture 

of healthy and defective mitochondria, with a 

unique distribution in the body. In most cases, 

mitochondrial disease is a multisystem disorder 

affecting more than one type of cell, tissue, 

or organ. 

Because muscle and nerve cells have especially 

high energy needs, muscular and neurological 

problems are common features of mitochondrial 

disease. Other frequent complications include 

impaired vision, cardiac arrhythmia (abnormal 

heartbeat), diabetes, and stunted growth. 

Usually, a person with a mitochondrial disease 
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has two or more of these conditions, some of 

which occur together so regularly that they are 

grouped into syndromes.

What causes mitochondrial 

myopathies?

Mitochondrial diseases are caused by genetic mutations. Genes provide the instructions 

for making proteins, and the genes involved in 

mitochondrial disease normally make proteins 

that work inside mitochondria. Within each 

mitochondrion, these proteins make up part of 

an assembly line that uses fuel molecules (sugars 

and fats) derived from food combined with 

oxygen to manufacture the energy molecule 

adenosine triphosphate, or ATP. 

Proteins at the beginning of the assembly line 

import sugars and fats into the mitochondrion 

and then break them down to provide energy. 

Proteins toward the end of the line—organized 

into five groups called complexes I, II, III, IV, 

and V—harness that energy to make ATP. This 

highly efficient part of the ATP manufacturing 

process requires oxygen, and is called the 

respiratory chain. Some mitochondrial diseases 

are named for the part of the respiratory chain 

that is affected, such as complex I deficiency.

A cell filled with defective mitochondria 

becomes deprived of ATP and can accumulate 

a backlog of unused fuel molecules and 

destructive forms of oxygen called free radicals 

or reactive oxygen species. These are the targets 

of antioxidant compounds (found in many foods 

and nutritional supplements) that appear to offer 

general defenses against aging and disease.
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In such cases, excess fuel molecules are used 

to make ATP by inefficient means, which can 

generate potentially harmful byproducts such 

as lactic acid. (This also occurs when a cell has 

an inadequate oxygen supply, which can happen 

to muscle cells during strenuous exercise.) The 

buildup of lactic acid in the blood—called lactic 

acidosis—is associated with muscle fatigue, and 

might damage muscle and nerve tissue.

Muscle and nerve cells use the ATP derived from 

mitochondria as their main source of energy. 

The combined effects of energy deprivation and 

toxin accumulation in these cells can lead to 

many muscular and neurological symptoms.

What are the symptoms of 

mitochondrial myopathy?

Myopathy

The main symptoms of mitochondrial myopathy 

are muscle fatigue, weakness, and exercise 

intolerance. The severity of any of these 

symptoms varies greatly from one person to the 

next, even in the same family.

In some individuals, weakness is most prominent 

in muscles that control movements of the eyes 

and eyelids. Two common consequences are 

the gradual paralysis of eye movements, called 

progressive external ophthalmoplegia (PEO), 

and drooping of the upper eyelids, called ptosis. 

Often, people automatically compensate for 

PEO by moving their head to look in different 

directions, and might not notice any visual 

problems. Ptosis can impair vision and cause a 

listless expression, but can be corrected by surgery.
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Mitochondrial myopathies also can cause 

weakness and wasting in other muscles of the 

face and neck, which can lead to difficulty with 

swallowing and, more rarely, slurred speech. 

People with mitochondrial myopathies also 

may experience muscle weakness in their 

arms and legs.

Exercise intolerance, also called exertional 

fatigue, refers to unusual feelings of exhaustion 

brought on by physical exertion. The degree 

of exercise intolerance varies greatly among 

individuals. Some people might have trouble 

only with athletic activities like jogging, while 

others might experience problems with everyday 

activities such as walking to the mailbox or 

lifting a milk carton.

Sometimes, mitochondrial disease is associated 

with muscle cramps. In rare instances it can lead 

to muscle breakdown and pain after exercise. 

This breakdown causes leakage of a protein 

called myoglobin from the muscles into the 

urine (myoglobinuria). Cramps or myoglobinuria 

usually occur when someone with exercise 

intolerance “overdoes it,” and can happen during 

the overexertion or several hours afterward.

While overexertion should be avoided, 

moderate exercise appears to help people with 

mitochondrial myopathy maintain strength. 

Encephalomyopathy

A mitochondrial encephalomyopathy typically 

includes some of the symptoms of myopathy 

plus one or more neurological symptoms. Again, 

these symptoms vary greatly among individuals 

in both type and severity.
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In addition to affecting eye muscles, a 

mitochondrial encephalomyopathy can affect 

the eye itself and parts of the brain involved 

in vision. For instance, vision loss, due to 

optic atrophy (shrinkage of the optic nerve) or 

retinopathy (degeneration of some of the cells 

that line the back of the eye), is a common 

symptom of mitochondrial encephalomyopathy.

Sensorineural hearing loss is a common 

symptom of mitochondrial diseases. It is caused 

by damage to the inner ear (the cochlea) or to 

the auditory nerve, which connects the inner 

ear to the brain. Sensorineural hearing loss 

is permanent but it can be managed through 

alternative forms of communication, hearing 

aids, or cochlear implants. Hearing aids amplify 

sounds before they reach the inner ear. Cochlear 

implants bypass damaged parts of the inner ear 

and stimulate the auditory nerve.

Mitochondrial diseases can cause ataxia, which 

refers to trouble with balance and coordination. 

People with ataxia are prone to falls, and may 

need to use supportive aids such as railings, 

a walker, or a wheelchair. Physical and 

occupational therapy also may help.

Other common symptoms of mitochondrial 

encephalomyopathy include migraine 

headaches and seizures. There are many 

effective medications for treating and helping 

to prevent migraines and seizures, including 

anticonvulsants and other drugs developed to 

treat epilepsy.
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Special issues in mitochondrial 

disease

Respiratory care

Mitochondrial diseases can affect the muscles 

or parts of the brain that support breathing. A 

person with mild respiratory problems might 

require occasional respiratory support, such 

as pressurized air. Someone with more severe 

problems might require permanent support 

from a ventilator. People should watch for signs 

of respiratory problems (such as shortness of 

breath or morning headaches) and have regular 

checkups with a respiratory specialist.

Cardiac care

Some mitochondrial diseases can cause 

cardiomyopathy (heart muscle weakness) or 

arrhythmia (irregular heart beat). Although 

dangerous, cardiac arrhythmia is treatable 

with a pacemaker, which stimulates a normal 

heartbeat. People with mitochondrial disorders 

may need to have regular examinations by a 

cardiologist.

Other potential health issues

People with a mitochondrial disease may 

experience gastrointestinal problems, diabetes, 

and/or kidney problems. Some of these problems 

are direct effects of mitochondrial defects in 

the digestive system, pancreas (in diabetes), 

or kidneys, and others are indirect effects of 

mitochondrial defects in other tissues. For 

example, myoglobinuria stresses the kidneys’ 

ability to filter waste from the blood and can 

cause kidney damage.
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What issues are of special concern 

in children?

Vision

Although gradual paralysis of eye movements 

(PEO) and ptosis typically cause only mild 

visual impairment in adults, they are potentially 

more harmful in children with mitochondrial 

myopathies.

Because the development of the brain is sensitive 

to childhood experiences, either PEO or ptosis 

during childhood can cause permanent damage 

to the brain’s visual system. It is important for 

children with signs of PEO or ptosis to have 

their vision checked by a specialist.

Developmental delays

Due to muscle weakness, brain abnormalities, 

or a combination of both, children with 

mitochondrial diseases may have difficulty 

developing certain skills. For example, they 

might take an unusually long time to reach 

motor milestones such as sitting, crawling, and 

walking. As they get older, they may be unable 

to get around as easily as other children their 

age, and may have speech problems and/or 

learning disabilities. Children affected by these 

problems may benefit from early intervention 

and services such as physical and speech therapy, 

and possibly an individualized education 

program at school.
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Are there specific treatments for the 

mitochondrial myopathies?

I

nstead of focusing on specific complications 

of mitochondrial disease, some treatments 

under investigation aim at fixing or bypassing 

the defective mitochondria. These treatments are 

nutritional supplements based on three natural 

substances involved in ATP production in 

our cells.

One substance, creatine, normally acts as a 

reserve for ATP by forming a compound called 

creatine phosphate (also called phosphocreatine). 

When a cell’s demand for ATP exceeds the 

amount its mitochondria can produce, creatine 

can release phosphate (the “P” in ATP) to rapidly 

enhance the ATP supply. In fact, creatine 

phosphate typically provides the initial burst of 

ATP required for strenuous muscle activity.

Another substance, carnitine, generally improves 

the efficiency of ATP production by helping 

import certain fuel molecules into mitochondria 

and cleaning up some of the toxic byproducts 

of ATP production. Carnitine is available as an 

over-the-counter supplement called L-carnitine.

Finally, coenzyme Q10, also called CoQ10 or 

ubiquinone, is a component of the mitochondrial 

respiratory chain (which uses oxygen to 

manufacture ATP). CoQ10 is also an antioxidant. 

Some mitochondrial diseases are caused by CoQ10 

deficiency, and CoQ10 supplementation is clearly 

beneficial in these cases. It might provide some 

relief from other mitochondrial diseases.
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Creatine, L-carnitine, and CoQ10 supplements 

often are combined into a “cocktail” for treating 

mitochondrial disease. Although there is a need 

for careful studies to confirm the value of this 

treatment, some people with mitochondrial 

disease have reported modest benefits. 

How are mitochondrial myopathies 

inherited?

The inheritance of mitochondrial diseases is complex, and often a mitochondrial 

myopathy can be difficult to trace through a 

family tree. In fact, many cases of mitochondrial 

disease are sporadic, meaning that they occur 

without any family history. 

To understand how mitochondrial diseases are 

inherited, it is important to know that there are 

two types of genes essential to mitochondria. 

The first type is housed within the nucleus—a 

compartment within our cells that contains most 

of our genetic material, or DNA. The second 

type resides exclusively within DNA contained 

inside the mitochondria.

Mutations in either nuclear DNA (nDNA) 

or mitochondrial DNA (mtDNA) can cause 

mitochondrial disease.

Nuclear DNA is packaged into structures 

called chromosomes—22 pairs of non-sex 

related chromosomes (called autosomes) and 

a single pair of sex chromosomes (XX in 

females and XY in males). This means that 

except for genes on the X chromosome, everyone 

has two copies of the genes in nDNA, with one 
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copy inherited from each parent. There are three 

inheritance patterns seen for diseases caused by 

nDNA mutations:

• Autosomal recessive means that it takes two 

mutant copies of a gene—one inherited from 

each parent—to cause the disease.

• Autosomal dominant means it takes just one 

mutant copy of a gene—inherited from one 

parent—to cause the disease.

• Usually, X-linked diseases appear only in 

males. An affected male’s mother and any 

daughters he has will carry the gene for the 

disease but typically will not have symptoms.

Unlike nDNA, mtDNA passes only from 

mother to child. This is because during 

conception, when the sperm fuses with the egg, 

the sperm’s mitochondria and its mtDNA are 

destroyed. Mitochondrial diseases caused by 

mtDNA mutations are unique because they are 

inherited in a maternal pattern. A mother can 

pass defective mtDNA to any of her children, 

but only her daughters—and not her sons—will 

pass it to the next generation.

Another unique feature of mtDNA diseases 

arises from the fact that a typical human cell 

contains only one nucleus but hundreds of 

mitochondria. A single cell can contain both 

mutant and normal mitochondria, and the 

balance between the two will determine the 

cell’s health, which can also explain the range 

of symptoms in mtDNA diseases. 
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The risk of passing on a mitochondrial disease 

to a child depends on many factors, including 

whether the disease is caused by mutations in 

nDNA or mtDNA. To find out more about 

these risks, talk with a doctor or genetic counselor.

What syndromes occur with 

mitochondrial disease?

Some syndromes associated with mitochondrial disease are:

Barth syndrome

Onset: infancy

Features: Typical symptoms include 

cardiomyopathy, general muscle weakness, and 

a low white blood cell count, which leads to an 

increased risk of infection. This syndrome was 

once considered uniformly fatal in infancy, but 

some individuals are now living much longer.

Inheritance pattern: X-linked

Chronic progressive external 

ophthalmoplegia (cPEO)

Onset: usually in adolescence or early adulthood

Features: PEO is often a symptom of 

mitochondrial disease. In some people, it is a 

chronic, slowly progressive condition associated 

with instability to move the eyes and general 

weakness and exercise intolerance.

Inheritance pattern: autosomal, but may occur 

sporadically 
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Kearns-Sayre syndrome (KSS)

Onset: before age 20

Features: PEO (usually as the initial symptom) 

and pigmentary retinopathy, a “salt-and-pepper” 

pigmentation in the retina that can affect vision. 

Other common symptoms include cardiomyopathy, 

conduction block (a type of cardiac arrhythmia) 

ataxia, short stature, neuropathy, and deafness.

Inheritance pattern: autosomal (mostly sporadic)

Leigh syndrome (MILS, or maternally 

inherited Leigh syndrome)

Onset: infancy or early childhood

Features: Brain abnormalities that can result in 

abnormal muscle tone, ataxia, seizures, impaired 

vision and hearing, developmental delays, and 

respiratory problems. Infants with the disease 

have a poor prognosis.

Inheritance pattern: maternal, autosomal 

recessive, X-linked

Mitochondrial DNA depletion syndromes 

(MDDS)

Onset: infancy

Features: A myopathic form of MDDS is 

characterized by weakness that eventually 

affects the respiratory muscles. Some forms of 

MDDS, such as Alpers syndrome, are marked 

by brain abnormalities and progressive liver 

disease. The anticonvulsant sodium valproate 

should be used with caution in children with 

Alpers syndrome because it can increase the risk 

of liver failure.

Inheritance pattern: autosomal
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Mitochondrial encephalomyopathy, 

lactic acidosis, and stroke-like episodes 

(MELAS)

Onset: childhood to early adulthood

Features: The hallmarks of MELAS are 

encephalomyopathy with seizures and/or 

dementia, lactic acidosis, and recurrent strokelike episodes. These episodes are not typical 

strokes, which are interruptions in the brain’s 

blood supply that cause sudden neurological 

symptoms. However, the episodes can produce 

stroke-like symptoms in the short term (such 

as temporary vision loss, difficulty speaking, 

or difficulty understanding speech) and lead to 

progressive brain injury. The cause of the strokelike episodes is unclear.

Inheritance pattern: maternal

Mitochondrial neurogastrointestinal 

encephalomyopathy (MNGIE)

Onset: usually before age 20

Features: This disorder is characterized by PEO, 

ptosis, limb weakness, and gastrointestinal 

(digestive) problems, including vomiting, 

chronic diarrhea, and abdominal pain. Another 

common symptom is peripheral neuropathy 

(a malfunction of the nerves that can lead to 

sensory impairment and muscle weakness).

Inheritance pattern: autosomal recessive
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Myoclonus epilepsy with ragged red fibers 

(MERRF)

Onset: late childhood to adolescence

Features: The most prominent symptoms of 

MERRF are myoclonus (muscle jerks), seizures, 

ataxia, and muscle weakness. The disease also 

can cause hearing impairment and short stature.

Inheritance pattern: maternal

Neuropathy, ataxia, and retinitis 

pigmentosa (NARP)

Onset: infancy to adulthood

Features: NARP is caused by an mtDNA 

mutation that is also linked to MILS, and the 

two syndromes can occur in the same family. 

In addition to the core symptoms for which it is 

named, NARP can involve developmental delay, 

seizures, and dementia. (Retinitis pigmentosa 

refers to a degeneration of the retina in the eye, 

with resulting loss of vision). 

Inheritance pattern: maternal

Pearson syndrome

Onset: infancy

Features: This syndrome involves severe anemia 

and malfunction of the pancreas. Children 

who have the disease usually go on to develop 

Kearns-Sayre syndrome.

Inheritance pattern: autosomal (often sporadic)
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How are mitochondrial diseases 

diagnosed?

The hallmark symptoms of mitochondrial myopathy include muscle weakness, exercise 

intolerance, impaired hearing and vision, ataxia, 

seizures, learning disabilities, heart defects, 

diabetes, and poor growth—none of which are 

unique to mitochondrial disease. However, a 

combination of three or more of these symptoms 

in one person strongly points to mitochondrial 

disease, especially when the symptoms involve 

more than one organ system.

To evaluate the extent of these symptoms, 

a physician usually begins by taking the 

individual’s medical history. Because 

mitochondrial diseases are genetic, a family 

history also is an important part of the 

diagnosis. Physical and neurological exams also 

will be part of the evaluation. 

The physical exam typically includes tests of 

strength and endurance, such as an exercise 

test (which can involve activities like repeatedly 

making a fist). The neurological exam can 

include tests of reflexes, vision, speech, and basic 

cognitive (thinking) skills.

Typically, the doctor will order laboratory 

tests to look for diabetes and liver and kidney 

problems. The doctor is likely to order an 

electrocardiogram (EKG) to check the heart for 

signs of arrhythmia and cardiomyopathy.

Tests may be ordered to look for abnormalities 

in the brain and muscles. Diagnostic imaging 

that produce detailed pictures of organs, bones, 

and tissues, such as computed tomography (CT) 

or magnetic resonance imaging (MRI), might 
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be used to inspect the brain for developmental 

abnormalities or signs of damage. In an 

individual who has seizures, the doctor might 

order an electroencephalogram (EEG), which 

involves placing electrodes on the scalp to record 

brain activity.

Since lactic acidosis is a common feature of 

mitochondrial disease, it is routine to test for 

elevated lactic acid in the blood and urine. 

Some cases might warrant measuring lactic 

acid in the cerebral spinal fluid (CSF) that 

fills spaces within the brain and spinal cord. 

The measurement can be made by collecting 

CSF through a spinal tap, or estimated by MR 

spectroscopy—a technique that uses an MRI 

signal to detect changes in the level of lactic 

acid and other chemicals in the brain.

One of the most important tests for mitochondrial 

disease is the muscle biopsy, which involves 

removing and examining a small sample of 

muscle tissue. When treated with a dye that 

stains mitochondria red, muscles affected by 

mitochondrial disease often show ragged red 

fibers—muscle cells (fibers) that have excessive 

mitochondria. Other stains can detect the 

absence of essential mitochondrial enzymes 

in the muscle. It also is possible to extract 

mitochondrial proteins from the muscle and 

measure their activity.

Noninvasive techniques can be used to 

examine muscle without taking a tissue 

sample. For instance, MR spectroscopy can 

be used to measure levels of the organic 

molecule phosphocreatine and ATP (which 

are often depleted in muscles affected by 

mitochondrial disease).
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Finally, genetic testing can determine whether 

someone has a genetic mutation that causes 

mitochondrial disease. These tests use genetic 

material extracted from blood or from a muscle 

biopsy. Although a positive test result can 

confirm diagnosis of a mitochondrial disorder, a 

negative test result can be harder to interpret. It 

could mean a person has a genetic mutation that 

the test was not able to detect.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) 

is to seek fundamental knowledge about the 

brain and nervous system and to use that 

knowledge to reduce the burden of neurological 

disease. The NINDS is a component of the 

National Institutes of Health (NIH), the leading 

supporter of biomedical research in the world. 

In conjunction with other NIH Institutes, 

private organizations, and industry, NINDS 

supports research focused on effective treatments 

and cures for mitochondrial myopathies and 

other mitochondrial diseases.

Scientists are investigating the possible 

benefits of exercise programs and nutritional 

supplements, primarily natural and synthetic 

versions of CoQ10. While CoQ10 has proven 

benefit for primary CoQ10 deficiency, it is 

unclear whether other nutritional supplements 

are useful for treating mitochondrial diseases.

Scientists have identified many of the genetic 

mutations that cause mitochondrial diseases. 

They have used that knowledge to create animal 

models of mitochondrial disease, which can 

be used to investigate potential treatments. 
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Scientists also have designed genetic tests that 

allow accurate diagnosis of mitochondrial 

defects and provide valuable information for 

family planning.

Most importantly, knowing the genetic 

mutations that cause mitochondrial disease 

opens up the possibility of developing 

treatments that are specifically targeted. One 

remarkable example where knowledge about 

mitochondrial disease genetics has led to a 

potential therapy is MNGIE. This syndrome is 

caused by genetic defects in an enzyme called 

thymidine phosphorylase (TP). Loss of the 

TP enzyme causes the body to accumulate 

metabolites called nucleosides. Some of these 

are the building blocks for DNA, and their 

accumulation appears to destabilize mtDNA. 

Researchers have shown that they can restore 

the enzyme and reduce nucleoside levels in 

the blood by giving individuals with MNGIE 

an infusion of blood-forming stem cells from 

a donor. Further study is needed to establish 

whether this treatment affects the clinical course 

of MNGIE.

Scientists hope to develop unique approaches to 

treating mitochondrial diseases through a better 

understanding of mitochondrial biology. The 

mitochondria in a single cell are not static; new 

mitochondria are born, old or damaged ones 

die, and two or more mitochondria can even 

fuse to become one. Because people affected 

by mitochondrial disease often have a mixture 

of healthy and mutant mitochondria in their 

cells, effective therapy could involve getting 

the healthy mitochondria to take over. It might 

be possible to rescue mutant mitochondria 
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by stimulating them to fuse with healthy 

mitochondria. Another approach might be 

to stimulate the birth of new mitochondria, 

encouraging the healthy ones to multiply and 

outnumber the mutants. Some diabetes drugs 

are known to stimulate new mitochondria, 

and are being eyed as potential treatments for 

mitochondrial disorders.

Finally, scientists have developed a potential way 

to prevent the passage of mutant mitochondria 

from mother to child. The approach would 

involve transferring the nDNA from a woman 

with mtDNA disease into another woman’s 

egg cell that has healthy mitochondria and has 

had its own nDNA removed. Then, standard 

assisted reproduction techniques could be used 

to fertilize this egg cell and implant it into the 

woman who donated the nDNA. Researchers 

have tested the approach in monkeys and 

shown that it can produce healthy offspring 

of an nDNA donor, with no signs of the 

donor’s mtDNA.

Where can I get more information?

For more information about mitochondrial diseases, other neurological disorders, or 

research programs funded by the NINDS, 

contact the Institute’s Brain Resources and 

Information Network (BRAIN) at:

BRAIN

P.O. Box 5801

Bethesda, MD 20824

301- 496-5751

800-352-9424

www.ninds.nih.gov
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Information about mitochondrial diseases is 

available from the following organizations:

Muscular Dystrophy Association

3300 East Sunrise Drive

Tucson, AZ 85718-3208

520-529-2000

800-572-1717

www.mda.org

National Organization for Rare Disorders 

(NORD)

55 Kenosia Avenue

Danbury, CT 06813-1968

203-744-0100 (voice mail)

800- 999-6673

www.rarediseases.org

United Mitochondrial Disease Foundation

8085 Saltsburg Road, Suite 201

Pittsburgh, PA 15239

412-793-8077

888-317-8633

www.umdf.org

Prepared by:

Office of Communications and Public Liaison

National Institute of Neurological 

Disorders and Stroke

National Institutes of Health

Department of Health and Human Services

Bethesda, Maryland 20892-2540

NIH Publication No. 15-6449 October 2015

NIH . . . Turning Discovery Into Health