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SHARE: Mitochondrial Disorders
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            What are mitochondrial disorders?

Mitochondrial disorders are caused by defects in mitochondria, which are energy factories found inside almost all the cells in the body. There are many types of mitochondrial disorders. They can affect one part of the body or many parts, including the brain, muscles, kidneys, heart, eyes, and ears.

Symptoms of mitochondrial disorders vary because a person can have a unique mixture of healthy and defective mitochondria, with a unique distribution of each within the body. In most cases, mitochondrial disorders affect 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 disorders. Other common symptoms include impaired vision, hearing loss, abnormal heartbeat (cardiac arrhythmia), diabetes, and stunted growth.

Mitochondrial disorders that mostly cause muscular problems are called mitochondrial myopathies ("myo" means muscle and "pathos "means disease), while mitochondrial disorders that cause both muscular and neurological problems are called mitochondrial encephalomyopathies (encephalo refers to the brain).

Mitochondrial myopathy

The main symptoms of mitochondrial myopathy are:

Muscle fatigue
	Weakness
	Exercise intoleranceThe severity of any of these symptoms varies greatly from one person to the next, even within the same family.

In some individuals, the weakness is most prominent in the muscles that control eye and eyelid movements. This can lead to these muscles eventually becoming paralyzed, called progressive external ophthalmoplegia (PEO). People with PEO also may experience a drooping of the upper eyelids, called ptosis. They also have difficulty moving their eyes up and down as well as side to side. Often, people automatically compensate for PEO by moving using their necks to look in different directions and might not notice any visual problems. Ptosis can impair vision and cause a listless expression. Surgery can help correct this.

Mitochondrial myopathies 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. In rare instances, this exercise intolerance can lead to muscle breakdown after exercise. This breakdown causes a protein called myoglobin to leak from a person’s muscles into their urine. The leakage, sometimes accompanied by muscle cramps, usually occurs when a person with exercise intolerance “overdoes it,” and can happen during physical activity or several hours afterward.

While people with mitochondrial myopathy should avoid overdoing it, moderate exercise can help them maintain strength.

Mitochondrial encephalomyopathy

Mitochondrial encephalomyopathy often includes some symptoms of myopathy, plus one or more neurological symptoms.

In addition to affecting the muscles around the eye, mitochondrial encephalomyopathy can affect the eye itself and parts of the brain involved in vision. For instance, vision loss, is a common symptom of mitochondrial encephalomyopathy. This can be caused by shrinkage of the optic nerve or a breakdown of the cells that line the back of the eye.

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.

Hearing loss is another common symptom of mitochondrial disorders. It is caused by damage to the inner ear or to the auditory nerve, which connects the inner ear to the brain. This kind of hearing loss is permanent, but it can be managed.  Alternative forms of communication (like sign language), hearing aids, or cochlear implants can help.

Mitochondrial disorders 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.

In some cases, mitochondrial disorders can lead to issues with breathing, heart health, kidney issues, diabetes, or digestive problems. People with mitochondrial disorders should get regular health check-ups to identify and monitor these potential problems.

Mitochondrial disorders in children

Although PEO and ptosis typically cause only mild visual impairment in adults, they can be much more harmful in children. During childhood, these conditions 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.

Children with mitochondrial disorders may have difficulty developing certain skills, due to either muscle weakness, neurological problems, or both. For example, they might take longer than is typical to learn to sit, crawl, or walk. As they get older, they may be unable to get around as easily as other children their age or may have problems with speech or learning. Children affected by these problems may benefit from early intervention and services such as physical and speech therapy or an individualized education program at school.

Who is more likely to get mitochondrial disorders?

Mitochondrial disorders are caused by genetic mutations. Genes provide the instructions for making proteins. The genes involved in mitochondrial disorders normally make proteins that work inside mitochondria. However, changes in these genes can cause problems with how the body makes important proteins.

The inheritance of mitochondrial disorders is complex. In fact, many cases are sporadic, meaning that they occur without any family history.

The risk of passing on a mitochondrial disorder to a child depends on many factors. To find out more about these risks, talk with a doctor or genetic counselor.

Health conditions such as Type 1 diabetes, cancer, multiple sclerosis, and Alzheimer’s disease can lead to secondary mitochondrial disease, which is not inheritable and cannot be passed on to a child.

Types of mitochondrial disorders

There are several conditions that fall under the umbrella of mitochondrial disorders. Some of the most common are listed below.

Barth syndrome

Barth syndrome is a rare, genetic disorder of lipid metabolism that primarily affects boys and men. Lipids are fat-like substances that are important parts of the membranes found within and between cells and in the myelin sheath that coats and protects the nerves. Symptoms of Barth syndrome may include reduced muscle tone (hypotonia) and muscle weakness, fatigue, undeveloped skeletal muscles, delayed growth, and methylglutaconic aciduria (an increase in an acid in the body that results in abnormal mitochondria function).

Chronic progressive external ophthalmoplegia

Chronic progressive external opthalmoplegia (also known as CPEO or just PEO) usually begins in a person’s adolescence or early adulthood.  PEO is often a symptom of mitochondrial disorders. In some people, it is a chronic, slowly progressive condition associated with inability to move the eyes, general body weakness, and exercise intolerance.

Kearns-Sayre syndrome****

Hallmarks of Kearns-Sayre Syndrome are PEO and pigmentary retinopathy, a “salt-and-pepper” pigmentation in the retina that can affect vision. Kearns-Sayre syndrome typically begins in before age 20 and is often accompanied by heart problems, progressive limitation of eye movements until there is complete immobility, and eyelid droop. Additional symptoms may include mild skeletal muscle weakness, heart block (a type of cardiac arrhythmia), short stature, hearing loss, an inability to coordinate voluntary movements (ataxia), impaired cognitive function, and diabetes.

Leigh syndrome

Leigh syndrome (also known as (MILS, or maternally inherited Leigh syndrome) usually begins in between the age of three months and two years. Rarely, it can occur in teenagers and adults.

Symptoms of Leigh syndrome usually progress rapidly, and may include loss of appetite, vomiting, irritability, loss of head control and motor skills, continuous crying, and seizures. As the disorder progresses, symptoms also may include generalized weakness, lack of muscle tone, and episodes of lactic acidosis (a buildup of lactic acid in the body), which can lead to problems with breathing and kidney function.

Mitochondrial DNA depletion syndromes

Mitochondrial DNA depletion syndromes (MDDS) begin in infancy and are characterized by weakness that eventually affects the muscles used to breathe. Some forms of MDDS are marked by brain abnormalities and liver disease that gets worse over time.  Alpers disease (also known as Alpers syndrome and Alpers progressive infantile poliodystrophy) is a rare, progressive disease. Most individuals with the disease develop symptoms in the first two years of life. For others, symptoms develop between age two and age 25. Symptoms of Alpers disease include liver disease, changes in brain function or structure associated with an infection, abnormal increase in muscle tone or stiffness (spasticity), involuntary jerking of a muscle or group of muscles (myoclonus), dementia or other cognitive changes, seizures, and loss of vision.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Beginning in childhood or early adulthood, the hallmarks of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (known as MELAS), are encephalomyopathy with seizures and/or dementia, lactic acidosis, and recurrent stroke-like episodes. These episodes are not typical strokes, but they 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 these episodes is unclear.

Mitochondrial neurogastrointestinal encephalomyopathy****

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) typically begins before age 20 and is characterized by PEO, ptosis, limb weakness, and 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).

Myoclonus epilepsy with ragged red fibers

Myoclonus epilepsy with ragged red fibers (MERRF), which begins in late childhood or adolescence,****features muscle jerks, seizures, ataxia, and muscle weakness. The disorder can cause hearing problems and short stature.

Neuropathy, ataxia, and retinitis pigmentosa

Neuropathy, ataxia, and retinitis pigmentosa (NARP) is caused by an mtDNA mutation that is also linked to MILS. The two syndromes can occur in the same family. Retinitis pigmentosa refers to a degeneration of the retina in the eye with resulting loss of vision. In addition to the core symptoms for which it is named, NARP can be associated with developmental delay, seizures, and dementia. NARP symptoms can begin anywhere from infancy to adulthood.

Pearson syndrome

Pearson syndrome involves severe anemia and problems with the pancreas. Pearson syndrome begins in infancy, and children who have it usually go on to develop Kearns-Sayre syndrome.

How are mitochondrial disorders diagnosed and treated?

Diagnosing mitochondrial disorders

A diagnosis generally includes:

An evaluation of medical and family history.
	Physical and neurological exams. 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.
	Laboratory tests to look for diabetes, liver and kidney problems, and elevated lactic acid in the blood and urine.  Lactic acid in the cerebral spinal fluid may be measured using a spinal tap or estimated via less invasive MRI imaging.
	EKG (electrocardiogram) to check the heart for signs of arrhythmia and cardiomyopathy.
	Diagnostic imaging, such as CT (computed tomography) or MRI to inspect the brain for developmental abnormalities or signs of damage. In an individual who has seizures, the doctor might order an EEG (electroencephalogram), which involves placing electrodes on the scalp to record brain activity.
	Genetic testing can determine whether someone has a genetic mutation.  Although a positive test result can confirm diagnosis of a mitochondrial disorder, a negative test result can be harder to interpret and does not definitively rule out the presence of a genetic mutation. It could mean a person has a mutation that the test was not able to detect.
	Muscle biopsy involves removing and examining a small sample of muscle tissue. When treated with a dye that stains mitochondria red, muscles affected by mitochondrial disorders 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. Genetic testing for mutations in mitochondrial DNA is more sensitive than testing for mutations in blood in certain mitochondrial disorders. Noninvasive techniques, such as MR spectroscopy, can be used to examine muscle without taking a tissue sample.Treating mitochondrial disorders

There are currently no cures or specific treatments for mitochondrial disorders. Generally, treatment is focused on managing symptoms and may include physical and occupational therapy, moderate, physician-led exercise programs, anti-seizure medications, heart medications, vitamins and supplements, or special diets. People with eye and vision symptoms may benefit from assistive devices and/or surgery, as can individuals with hearing loss. People with any of the special issues mentioned below should be monitored by their healthcare provider to track their symptoms and identify any appropriate treatments.

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.

Some mitochondrial disorders may cause cardiomyopathy (heart muscle weakness) or arrhythmia (irregular heartbeat).  Although dangerous, cardiac arrhythmia is treatable with a pacemaker, which stimulates a normal heartbeat.

People with a mitochondrial disease may experience gastrointestinal problems, diabetes, and/or kidney problems. These associated conditions and disorders should be managed with appropriate treatments for each. While some of these problems are directly related to mitochondrial disorders, others may be indirectly affected by the disorder. For example, having myoglobin in a person’s urine causes the kidneys to work harder to filter it out, which in turn can lead to kidney damage.

What are the latest updates on mitochondrial disorders?

NINDS, a component of the National Institutes of Health (NIH), supports research focused on finding effective treatments for mitochondrial disorders.

Scientists hope to develop unique approaches to treating mitochondrial disorders through a better understanding of mitochondrial biology. Because people affected these disorders often have a mixture of healthy and unhealthy mitochondria in their cells, effective therapy could involve encouraging the healthy mitochondria to make up for the unhealthy mitochondria. This might include stimulating the damaged mitochondria 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 unhealthy ones.

Scientists have identified many of the genetic mutations that cause mitochondrial disorders. They have used that knowledge to create animal models, which can help researchers investigate potential treatments. They have also developed genetic tests to support accurate diagnosis of mitochondrial disorders and provide valuable information for family planning. Knowing the genetic mutations that cause these disorders opens up the possibility of developing specifically targeted treatments for them.

The NIH-supported North American Mitochondrial Disease Consortium (NAMDC) is a network of clinicians and researchers involved in mitochondrial research. NAMDC maintains a patient registry to standardize diagnostic criteria, collect clinical data, and facilitate participation in research studies. The group has also established a repository for specimens and DNA from people with mitochondrial disorders which is available to qualified researchers.

Researchers funded by NINDS are working to determine the safest and most effective dosage of an amino acid, called citrulline, that may be used treat adults with MELAS. Once the dosage is established, it can be used in future clinical trials.

Investigators funded by NINDS are conducting a natural history study of MNGIE to learn more about the disorder and develop valuable outcomes measures for use in future clinical trials. In another NINDS-supported study, scientists are using two interventions—Promoting Resilience in Stress Management (known as PRISM) and a clinical-focused narrative—to determine the best way to help people with mitochondrial disorders deal with the stress of their condition and help them build resilience in managing their condition.

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Learn About Clinical Trials

Clinical trials are studies that allow us to learn more about disorders and improve care. They can help connect patients with new and upcoming treatment options.

How can I or my loved one help improve care for people with mitochondrial disorders?

Consider participating in a clinical trial so clinicians and scientists can learn more about mitochondrial disorders. Clinical research uses human study participants to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.

All types of participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with mitochondrial disorders at Clinicaltrials.gov.

*NINDS acknowledges Dr. Anthony A. Amato and the American Academy of Neurology for their contributions to this piece.*

Where can I find more information about mitochondrial disorders?

Information may be available from the following resources:

Barth Syndrome Foundation 
Phone: 914-303-6323

Cure Mito Foundation
Phone: 646-483-7073

Epilepsy Foundation
Phone: 301-459-3700 or 800-332-1000; 866-748-8008 Spanish

Genetic and Rare Diseases (GARD) Information Center

MitoAction
Phone: 888-648-6228

Muscular Dystrophy Association
Phone: 800-572-1717

National Organization for Rare Disorders (NORD)
Phone: 203-744-0100

United Mitochondrial Disease Foundation
Phone: 412-793-8077 or 888-317-8633
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