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 copy inherited from each parent. There are three inheritance patterns seen for diseases caused by nDNA mutations:
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.
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
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
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 stroke-like 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 stroke-like 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
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)
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 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).
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. 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 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.