13. How do you diagnose mitochondrial disease?

Biochemical Tests

These tests involve taking samples of body fluids, like blood, urine or cerebrospinal fluid (CSF) and are usually the first tests performed.

Elevated Lactate

Often (but not always), mitochondrial disease patients suffer from a condition known as lactic acidosis, which is an increase in lactic acid concentration in the body.

It is common, therefore, to have the levels of lactate measured to see if these are abnormal. High levels of lactate, along with other symptoms, typically do indicate a mitochondrial problem, however elevated blood lactate can also be seen after vigorous exercise or in other non related conditions which can confuse things.

To complicate matters even more, elevated levels of lactate are not seen in all types of mitochondrial diseases, which means that a normal result does not rule out mitochondrial disease.


Mitochondrial disease is most frequently caused by faulty proteins within the respiratory chain which reduce energy production so it is important to pinpoint the source of the problem.

Enzymology tests measure the activity of these proteins. The function or activity of each of the five protein complexes of the respiratory chain is tested using biochemical reactions to identify which proteins are faulty.

These enzymology tests require a biopsy, typically muscle, to measure the activity of the protein complexes. Further information on biopsies is provided under ‘Histochemical Tests’ below.

Amino Acids & Organic acids

Urine can also be tested for levels of certain amino acids, proteins and organic acids which might indicate Mitochondrial Disease.

Histochemical Tests - using a biopsy

Doctors might also take a piece of tissue (biopsy) and examine the chemicals within it. This is usually a muscle biopsy as this is the easiest to obtain, but occasionally liver or skin may be sampled depending on the symptoms of the disease.

This procedure is quite invasive and will usually require a general anesthetic in a child which may not be advised. Results are usually not available for at least six weeks after the biopsy has been taken.

At this level of analysis, the appearance (histology) of the tissue is tested. Chemical staining may reveal abnormalities like 'ragged red fibres' which are abnormal mitochondria beneath the muscle membrane (although these are rarely seen in children under 5) or COX negative fibres indicating deficiency of cytochrome oxidase or COX (an enzyme essential for completing the respiratory chain). 

Although these can both be a characteristic of mitochondrial disease, their absence doesn’t exclude Mitochondrial Disease as it may just be, the piece of tissue examined did not contain a sufficient number of the faulty mitochondria to detect a problem. In these cases doctors usually rely on looking at all the symptoms and what is the most likely diagnosis.

Neurological Evaluation 

Some types of mitochondrial disease show specific patterns of change on a MRI (Magnetic Resonance Imaging) brain scan.  Symmetrical lesions in the area known as the basal ganglia are common, as is atrophy (decrease in size) of certain areas.

MRS (Magnetic Resonance Spectroscopy) is able to identify metabolic changes and may be able to identify elevated levels of lactate in the brain.

Nerve conduction tests may be useful in diagnosing neuropathy and EMG (Electromyography) can help diagnose myopathy.

Cardiac Evaluation

Electrocardiography and echocardiography may reveal certain heart conditions such as a conduction disorders or cardiomyopathy.

Ophthalmological Testing (Visual)

Electroretinography is helpful for measuring optic nerve thickness and range of eye movements and may be helpful in diagnosing eye conditions such as retinitis pigmentosa.

Genetic Testing

The ultimate goal in diagnosing Mitochondrial Disease is to find the exact genetic mistake, or mutation responsible. A specific mutation at a specific location provides important information about the type of mitochondrial disease and distinguishes it from other diseases that may have similar characteristics.

Mitochondrial disease may be due to genetic mutation(s) in either the mitochondrial genome (a small molecule of DNA present in multiple copies in the mitochondria) or the nuclear genome (the chromosomes in the cell nucleus which contain the vast majority of our DNA).

Many different testing methods can be used to detect different genetic mutations, and a stepwise approach is usually adopted, starting with testing for more common mutations and genes. If a common mutation is not identified, then testing can be complex and may take a long time.

In recent years, Next Generation Sequencing has revolutionised genetic testing by providing much more extensive testing in a shorter timeframe. These techniques are continuing to be developed and improved, thereby providing a genetic diagnosis to many more families.

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