Mitochondrial Disease

Mitochondrial disease is not a single disorder but an umbrella term for dozens of individual disorders in which the body’s cells have problems producing energy. Together, these disorders affect between 1 in 6,000 and 1 in 8,000 live births, making mitochondrial disease almost as common as childhood cancer. Individually though, these conditions are very rare. Mitochondrial disorders are frequently called mitochondrial encephalomyopathies and include the following conditions, as well as many others:

• Kearns Sayre syndrome
• Leigh's disease
• MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
• MERRF (myoclonic epilepsy with ragged red fibers)
• MNGIE (mitochondrial neurogastrointestinal encephalopathy)
• Pearson syndrome
• Disorders of pyruvate metabolism, such as pyruvate dehydrogenase deficiency
• Disorders of the Krebs cycle

Mitochondrial disorders are genetic and sometimes run in families. They can cause a wide range of symptoms, from developmental delay and hearing loss to seizures, strokes, heart failure and diabetes, in differing combinations. Multi-organ involvement is typical for these disorders. Disease can range from severe, starting at birth, to mild disease that doesn’t become apparent until adulthood. Sometimes it can appear abruptly when the child is challenged by another illness.

There is currently no cure for mitochondrial disease. Treatment consists mainly of supportive therapy along with some vitamins and supplements. Treatments are individualized depending on which mitochondrial disorder and what symptoms a child has. Since children with mitochondrial disease are very sensitive to even minor illnesses and other stressors, it is important to keep close tabs on your child's overall health and work closely with specialists to ensure the best care for the "whole child.”

For more about how we manage mitochondrial disease at Boston Children’s, visit the Mitochondrial Program page.

Because mitochondria are in every cell of the body, mitochondrial disorders can affect many different body systems and cause a wide variety of symptoms in different combinations. This can make them challenging to diagnose.

The parts of the body that tend to be most affected are those that need the most energy, such as the heart, brain, muscles and gastrointestinal tract. Symptoms can range from fatigue and exercise intolerance to hearing loss, seizures, strokes, heart failure, diabetes and kidney failure. A large majority but not all children with mitochondrial disorders have developmental delay.

Depending on the severity of the disorder, symptoms can appear at birth or they may not appear until adulthood. In some children, mitochondrial disease progresses quickly and can be severe. In others, it can be stable and well-managed for many years. Sometimes symptoms begin suddenly, triggered by another illness.

Mitochondria are the “power plants” of all the cells in the human body, producing the energy our bodies need to function. They are also involved in metabolism, helping our cells build, break down and recycle compounds they need.

In mitochondrial disorders, the mitochondria’s ability to do these jobs is impaired because of a genetic mutation — a “mistake” in the DNA. We all have two types of DNA in our bodies. The nuclear DNA (usually just called “DNA”) is found in the cell's nucleus and is inherited from both our mother and father. Mitochondria also have DNA, inherited from mothers. Because both types of DNA are responsible for the structure and function of the mitochondria, mutations in either can cause mitochondrial disorders. Mutations can be inherited from parents or can happen for the first time in a child (so-called de novo mutations).

Inherited mutations in the mitochondrial DNA come from the mother. Mutations in nuclear DNA usually are recessive, meaning that one copy of the mutation comes from each parent. In this case, the parents are just carriers and do not have mitochondrial disease themselves. This also explains why some people with a mitochondrial disorder have a family history of the disorder, while others are the only one in their family to be affected.

For more on mitochondrial disease, visit our FAQ page.

Because symptoms are so varied, affecting multiple organs in the body, diagnosing mitochondrial disease can be challenging. Sometimes other disorders not involving the mitochondria are mistakenly diagnosed as mitochondrial disease. The opposite is true as well: Sometimes individuals who truly have mitochondrial disease are diagnosed as having something else.

Many symptoms of mitochondrial disease, such as failure to thrive, short stature, poor stamina, developmental delay, seizures, poor muscle tone, vomiting, severe constipation, or diarrhea, have a variety of other causes. Because of this, it’s usually not a single symptom but a combination of two, three or more different symptoms that leads clinicians to suspect mitochondrial disease.

Genetic testing is the most reliable way to diagnose and categorize a mitochondrial disorder. We may recommend genetic testing for your child (and sometimes for parents too) if any of these symptoms are present:

• Developmental delay with involvement of other organs
• Dardiomyopathy (disease of the heart muscle) or unexplained heart block, or impaired electrical signals in the heart
• High levels of lactate in the blood or cerebrospinal fluid, when other symptoms are present
• Certain abnormal findings on brain imaging
• Ophthalmoplegia (impaired eye movement) or ptosis (drooping upper eyelid)
• Hearing loss
• Severe gastrointestinal dysmotility (weak or lost muscular contractions in the intestines) or intestinal pseudo-obstruction (bowel obstruction caused by inability of the intestine to push food through)
• Significant developmental regression in the setting of an illness

Genetic testing often begins with analyzing the mitochondrial DNA and, if results are negative, testing the nuclear DNA for genes known to be involved in mitochondrial disease. If these tests come up negative, the child’s nuclear DNA may need to be completely analyzed through whole exome sequencing (this is similar to whole genome sequencing, but analyzes just the genes that code for proteins).

The type and depth of genetic testing we recommend will depend on the child’s symptoms and how strongly we suspect mitochondrial disease. Unfortunately, at this writing, extensive genetic testing is not always covered by insurance. If you or your child is in need of testing, we will work with your insurance companies to help with the process of approval.

Additional, non-genetic tests also help in diagnosing mitochondrial disorders. They include:

• Biochemical tests on urine, blood and spinal fluid
• A muscle biopsy to examine the mitochondria and test enzyme levels
• Magnetic resonance imaging (MRI) of the brain and spine

If a mitochondrial disorder is suspected or identified, we may refer your child for further testing and consultations with specialists. Testing depends on symptoms, and may include:

• Echocardiogram
• Electrocardiogram (EKG)
• Eye examinations
• Hearing tests

Managing your child's condition

While mitochondrial disorders have no cure, children often do better when symptoms are caught and addressed early. Your child will be followed closely and screened for a variety of conditions related to mitochondrial disease, such as heart, vision, and hearing problems. Symptoms can often be alleviated by maintaining good general health, including careful attention to nutrition and avoiding infections and dehydration.

Exercise is one of the few proven methods for improving mitochondrial functioning and can help preserve your child’s strength and endurance. Exercise regimens should be supervised, should build up very gradually in intensity and should be suspended during illness.

Currently, vitamins and supplements are the mainstay of treatment for mitochondrial disorders. They are thought to help mitochondria produce energy and reduce accumulation of toxic compounds inside cells. These supplements and cofactors are sometimes given together in “cocktails.” At present, the compounds that have been most well tested include coenzyme Q10 and creatine, but we also use a great variety of other supplements.

Regimens for specific mitochondrial disorders may include compounds that are deficient because of the disease, such as arginine (in MELAS) and folinic acid (in Kearns-Sayre syndrome). At Boston Children’s, we are testing dichloroacetate (DCA), which counters the high levels of lactic acid found in some mitochondrial disorders. In certain disorders, we may prescribe a special diet.

Supportive care

Because children with mitochondrial disease tend to be very sensitive to the stresses caused by minor illnesses like colds and fevers, your clinician will sometimes prescribe additional supportive therapies when the child is sick. These can include vitamins, cofactors, medications to counter biochemical imbalances that may occur, beverages containing electrolytes and sometimes intravenous (IV) hydration and IV antibiotics. In some instances, your child may need to be monitored in the hospital.

Children with mitochondrial disease also are known to be sensitive to a variety of drugs, as well as anesthetics used for surgical procedures.