Mitochondrial Myopathies (MM)

Diagnosis

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 symptoms involve more than one organ system. Since symptoms often overlap with many other conditions, diagnosis can be challenging.

To assess the possibility of mitochondrial disease, a physician usually begins with a careful medical and family history (including at least three generations to identify hereditary patterns), followed by a detailed physical and neurological exam. Based on findings, further specialized evaluation may be pursued.

Diagnostic testing

Expert recommendations emphasize a combination of genetic, biochemical, and tissue-based tests, when needed. No single symptom or test can diagnose mitochondrial disease by itself.

Genetic testing (recommended first when possible)
Current guidelines recommend beginning with broad genetic testing because many mitochondrial diseases can be identified this way.

• Comprehensive testing usually includes full mitochondrial DNA (mtDNA) sequencing and nuclear gene testing with a focus on genes known to affect mitochondrial function. These tests look for changes (mutations) that can disrupt how mitochondria work.
• If blood testing is normal but symptoms strongly suggest mitochondrial disease, doctors may test mtDNA from another tissue such as urine, cheek cells, or muscle. This is because the amount of mutated mtDNA can vary from one tissue to another (a concept called heteroplasmy).
• A positive genetic test can confirm the diagnosis.
• A negative genetic test does not rule out mitochondrial disease, because some mutations are still unknown or difficult to detect.

Biochemical testing (blood, urine, and sometimes cerebrospinal fluid)
These tests look for patterns that suggest problems with energy production.

Common biochemical tests include:

• Lactate and pyruvate: Mitochondrial dysfunction can cause these levels to rise. The lactate/pyruvate ratio helps doctors understand whether the issue is likely related to the mitochondria.
• Amino acids: Certain amino acids, especially alanine, may be elevated when mitochondria are not working properly.
• Acylcarnitines: These help show whether the body is having trouble processing fats for energy.
• Urine organic acids: Can reveal by-products that build up when energy pathways are disrupted.
• Routine laboratories such as a complete blood count (CBC), creatine kinase (CK), liver enzymes, and albumin can show stress on muscles or other organs.

These tests can support a diagnosis, but they are not conclusive on their own because results can be influenced by illness, exercise, diet, or how the sample was handled.

Muscle biopsy (used only when genetic testing is inconclusive or more detail is needed)
Muscle biopsy is no longer the first test doctors turn to, but it can still be helpful in specific situations, as follows:

• Genetic testing does not find a clear answer.
• Low-level mtDNA mutations are suspected but not seen in blood or urine.
• Another disorder needs to be ruled out.

A biopsy involves taking a small sample of muscle tissue. This sample can then be evaluated in several ways:

• Special stains can highlight areas where mitochondria are abnormal or missing important enzymes.
• Biochemical tests can measure how well mitochondrial enzymes are working.
• Electron microscopy can show the shape and structure of mitochondria in detail.

It is important to note that some people with mitochondrial disease have normal-looking muscle biopsies, so a normal biopsy does not rule out the condition.

Imaging and other organ evaluations
These tests help identify which organs are involved, which can guide diagnosis and management.

• Magnetic Resonance Imaging (MRI) or Magnetic Resonance Spectroscopy (MRS) of the brain: Looks for brain changes and can measure certain chemicals, such as lactate, that may indicate mitochondrial dysfunction.
• Electroencephalogram (EEG): Records electrical activity in the brain and is used to evaluate seizures or unusual neurological events.
• Electrocardiogram (EKG/ECG) or echocardiogram: Checks heart rhythm (EKG/ECG) and heart structure/pumping function (echocardiogram) to detect possible cardiac involvement.
• Kidney and liver function tests: Blood and urine tests that show how well these organs are working and whether mitochondrial issues may be affecting them.

These tests provide important clues but cannot diagnose mitochondrial disease by themselves. Instead, they help build the overall picture of how the disease affects the body.

Additional reading

• Mancuso M. et al. 280th ENMC workshop study group. 280th ENMC International Workshop: The ERN EURO-NMD mitochondrial diseases working group; diagnostic criteria and outcome measures in primary mitochondrial myopathies. Hoofddorp, the Netherlands, 22-24 November 2024. Neuromuscul Disord. 2025 May;50:105340. doi: 10.1016/j.nmd.2025.105340.
• 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

Last reviewed May 2026.