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Mitochondrial Myopathies (MM)


None of the hallmark symptoms of mitochondrial disease — muscle weakness, exercise intolerance, hearing impairment, ataxia, seizures, learning disabilities, cataracts, heart defects, diabetes, and stunted growth — are unique to mitochondrial disease. However, a combination 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 patient’s personal medical history (a detailed family history including at least three generations is essential to assess hereditary patterns), and then proceeds with physical and neurological exams. At the bottom of this page is a table that explains in detail these tests and what they are expected to show.

Diagnostic tests in mitochondrial diseases

A physical exam typically includes tests of strength and endurance, such as an exercise test, which can involve activities like repeatedly making a fist, or climbing up and down a small flight of stairs. A neurological exam can include tests of reflexes, vision, speech, and basic cognitive (thinking) skills.

Depending on information found during the medical history intake and exams, a physician might proceed with more specialized tests that can detect abnormalities in muscles, brain, and other organs.1

The most important of these tests is the muscle biopsy, which involves removing a small sample of muscle tissue to examine. When treated with a dye that stains mitochondria, 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 is also possible to extract mitochondrial proteins from the muscle and measure their activity. In most cases, genetic studies should be obtained before invasive testing such as muscle biopsy, thus, muscle biopsy is suggested when genetic testing cannot confirm the diagnosis or when required to rule out other conditions in the differential diagnosis. The main limitation of muscle biopsy in the diagnosis of mitochondrial myopathies is that it may be normal or show only minimal abnormalities for certain mitochondrial defects.

In addition to the muscle biopsy, noninvasive techniques can be used to examine muscle without taking a tissue sample. For instance, a technique called muscle phosphorus magnetic resonance spectroscopy (MRS) can measure levels of phosphocreatine and ATP (compounds that are often depleted in muscles affected by mitochondrial disease).

CT scans and MRI scans can be used to visually inspect the brain for signs of damage, and surface electrodes placed on the scalp can be used to produce a record of the brain’s activity called an electroencephalogram (EEG).

Similar techniques might be used to examine the functions of other organs and tissues in the body. For example, an electrocardiogram (EKG) can monitor the heart’s activity, and a blood test can detect signs of kidney malfunction.

Finally, a genetic test can determine whether someone has a genetic mutation that causes mitochondrial disease. Ideally, the test is done using genetic material extracted from blood or from a muscle biopsy. It is important to realize that although a positive test result can confirm diagnosis, a negative test result is not necessarily conclusive.

Diagnostic Tests in Mitochondrial Diseases

Type Test What it Shows

Family history

Clinical exam or oral history of family members

Can sometimes indicate inheritance pattern by noting “soft signs” in unaffected relatives. These include deafness, short stature, migraine headaches, and PEO.

Muscle biopsy

1. Histochemistry

2. Immunohistochemistry

3. Biochemistry

4. Electron microscopy

1. Detects abnormal proliferation of mitochondria and deficiencies in cytochrome c oxidase (COX, which is complex IV in the electron transport chain).

2. Detects presence or absence of specific proteins. Can rule out other diseases or confirm loss of electron transport chain proteins.

3. Measures activities of specific enzymes. A special test called polarography measures oxygen consumption in mitochondria.

4. May confirm abnormal appearance of mitochondria, though not used often today.

Blood enzyme test

1. Lactate and pyruvate levels

2. Serum creatine kinase

1. If elevated, may indicate deficiency in electron transport chain; abnormal ratios may help identify the part of the chain that is blocked.

2. May be slightly elevated in mitochondrial disease but usually only high in cases of mitochondrial DNA depletion.

Genetic test

1. Known mutations

2. Rare or unknown mutations

1. Uses blood sample or muscle sample to screen for known mutations, looking for common mutations first.

2. Can also look for rare or unknown mutations but may require samples from family members; this is more expensive and time-consuming.

Other tests

·Complete blood count

·Serum creatine kinase (CK) and uric acid

·Serum transaminases

·Serum albumin

·Serum lactate and pyruvate

·Lactate/pyruvate ratio if serum lactate is elevated

·Serum amino acids (for elevated alanine)

·Serum acylcarnitine (low free carnitine and elevated acyl/free carnitine ratio are suggestive of disrupted fatty acid oxidation)

·Serum and urine 3-methylgluticonic acid

These tests are suggested by the consensus-based expert recommendations for the evaluation and diagnosis of mitochondrial disease published in 2014.2


  1. Nardin, R. A. & Johns, D. R. Mitochondrial dysfunction and neuromuscular disease. Muscle and Nerve (2001). doi:10.1002/1097-4598(200102)24:2<170::AID-MUS30>3.0.CO;2-0
  2. Parikh, S. et al. Diagnosis and management of mitochondrial disease: A consensus statement from the Mitochondrial Medicine Society. Genetics in Medicine (2015). doi:10.1038/gim.2014.177

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