Frequency

Mitochondrial disease or cytopathy (from cyto-, cell, and -pathy, disease) is not uncommon. In three large population studies, approximately 1 person in 9,000 had either a disease-causing mitochondrial DNA mutation or another mitochondrial defect. Adults tend to have mitochondrial DNA mutations, whereas children have more defects of other types causing their illness.

It is likely, however, that mitochondrial disease is more frequent than these studies suggest. They did not include patients with certain types of defects (substrate, coenzyme Q10, and cytochrome b1 deficiencies; protein transport defects; protein assembly and Krebs cycle defects). Some have estimated that 1 in 2000 to 3000 people has mitochondrial disease.

Symptoms

In the simplest terms, mitochondrial disease or cytopathy can ultimately be thought of as a deficiency of energy production. The other cell-specific functions that mitochondria perform may also give rise to disease symptoms, however. The degree of mitochondrial dysfunction, the organs involved, and environmental conditions (for instance, whether the person has another chronic illness) will determine the severity of the disease.

One factor in the variety of characteristics of these diseases is their many different causes:

• inherited mutations in mitochondrial DNA or nuclear DNA
• spontaneous mutations in mitochondrial DNA or nuclear DNA
• environmental toxins
• medications used to treat other diseases

Another factor is that problems with mitochondrial function may affect only certain organs, for reasons that are not entirely clear. A partial explanation for the difference may be that some tissues or organs (such as skin) have low energy requirements for functioning, whereas others (such as nerve cells) have high energy requirements. Nerve cells thus would be more sensitive to changes in energy. Variability may also be due to the person's stage of development. A growing and developing organ needs more energy than one that is mature, so subtle defects in energy metabolism would have a greater impact on a developing organ. Other variability may be due to processes that we do not yet understand.

Genetics

Mitochondrial inheritance

All mitochondria come from the mother’s egg. The egg destroys the mitochondria in the sperm. It would seem reasonable to assume that if the mother’s mitochondrial DNA has a particular disease-causing mutation, then all mitochondria would have the same mutation and the disease associated with this mutation would be relatively similar from patient to patient. This does NOT occur, however. It is very rare for all mitochondrial DNA copies to have a specific mutation in a particular patient. Usually some of the mitochondria carry the mutation and the others are normal. This is called heteroplasmy.

Each child will carry the mother’s mitochondrial DNA mutation, although in different amounts. Varying percentages of mutated and normal mitochondria can change the severity and characteristics of a particular disease.

Genocopy and phenocopy

The interplay among the many genes and cells that must cooperate for cells to function is complex. Changes in this interaction can influence changes in the metabolic state produced by a particular mutation. These processes produce a spectrum of disease presentations, and can give rise to one hallmark of mitochondrial disease—identical mitochondrial DNA mutations may not produce identical diseases. This is called phenocopy.

On the other hand, different mutations may produce disorders that appear the same. This is called genocopy. In fact, mutations in nuclear DNA can give rise to syndromes that have the clinical features of a particular mitochondrial DNA mutation. For instance, patients with the disease syndrome called MELAS (mitochondrial myopathy, progressive encephalopathy, lactic acidosis, and stroke-like episodes) usually have a particular mitochondrial DNA mutation, but some have dysfunction of the mitochondria's energy-producing mechanism (electron transport chain complexes) instead.

Diagnosis

The wide array of signs and symptoms of mitochondrial disease can make the physician’s head spin. No single symptom, sign, or test result points directly to a mitochondrial cytopathy. A patient can have a perfectly normal muscle biopsy and still have a disease-causing mitochondrial DNA mutation causing symptoms. Some doctors follow this rule: “When a common disease has features that set it apart from the pack, or when it involves three or more organ systems, think mitochondria.”*

Diagnostic testing

If no single test defines a mitochondrial cytopathy, how can it be detected or defined? Many tests are evaluated together with the patient’s symptoms. Blood tests are performed to check serum levels of lactate, pyruvate, amino acids, and coenzyme Q10, and the acyl carnitine profile. Organic acids in the urine are evaluated. Magnetic resonance imaging (MRI) of the brain is also performed. Many centers now perform a new variation of the MRI, magnetic resonance spectroscopy (MRS). MRS gives the physician a real-time biochemical analysis of various areas of the brain. It can suggest a defect in oxidative phosphorylation within the brain, by the presence of lactate peaks.

Muscle biopsy

If the results of the previous tests suggest a mitochondrial disease, then a muscle biopsy is performed (see photo). The most common site of muscle biopsy is the thigh muscle, vastus lateralis. Other muscles, including the heart, can be tested (as well as samples from the skin, liver, and blood), but fewer results are available for comparison to identify abnormalities.

Photo courtesy of Dr. Russell P. Saneto

Muscle mitochondria, in a photograph taken using an electron microscope. These mitochondria are from a 11-year old boy with MELAS. The mitochondria are enlarged, with thickened inner cristae.

A small sample of muscle tissue is analyzed using an electron microscope and stains to show chemicals and enzymes inside the cells:

• electron transport chain complex enzymatic analysis, to show the activity of complex I, II, III, and IV
• antibodies that bind to specific proteins in muscle tissue, to detect the presence and quantity of that protein in the muscle.
• chemical stains to detect changes in mitochondrial numbers or function (for example, Gomori trichrome stain to show “ragged-red fibers” in mitochondrial disease)

If fresh muscle is used, polarography (a test using electrical current to detect oxygen use) is also used to investigate the functioning of the electron transport chain complexes and the efficiency of complex I, II, III, IV, and V. The use of fresh muscle and polarography is the only way that complex V function can be analyzed.

The muscle biopsy is also used to look for possible mitochondrial DNA mutations, using processes called restriction mapping or sequencing.

Why examine muscle tissue?

There are several reasons to examine muscle tissue for changes in mitochondrial structure, numbers, and electron transport chain activity:

• Muscle cells generally do not undergo cell division after birth. (Although the number of muscle cells remains the same, they change in size with use or disuse.) For this reason, mitochondrial abnormalities tend to collect and be more apparent in muscle cells. Cell division can select against the survival of abnormal cells.
• Muscle tissue is easily accessible.
• Many patients with a mitochondrial cytopathy have muscle involvement.

When the brain is involved, the physicians can only speculate about whether what is found in muscle tissue is also found in brain tissue.

*From Dr. Robert Naviaux, Associate Professor, University of California San Diego, School of Medicine.

By Russell P. Saneto, D.O., Ph.D., Children’s Hospital and Regional Medical Center/University of Washington School of Medicine, Seattle, WA.

Topic Editor: Russell P. Saneto, D.O.,Ph.D.
Last Reviewed:6/24/04