Diagnostic Challenges

  • There are many different clinical presentations within Mitochondrial Disease and the condition often mimics other conditions which adds complexity to diagnosis. For example, problems with eye movement are a common symptom of Mitochondrial Disease however many different diseases cause similar symptoms which inevitably leads to a delay in diagnosis, until other causes are ruled out.
  • For some conditions, it remains a real challenge to detect the mitochondrial abnormality. This might be because the biochemical change that we see is very subtle, or alternatively because each patient with Mitochondrial Disease could have any one (or more) of many, many hundreds of possible different causative genetic changes. The identification of these changes can be like searching for a needle in a haystack.
  • It is now believed that about 2,000 proteins (or building blocks) are required to make a mitochondrion work. A defect could theoretically affect any of these building blocks and many of the building blocks themselves have not been properly identified in human subjects. This means that both doctors and scientists still have a lot to learn even about the way mitochondria work. Finding abnormalities of mitochondrial function, defining the pathological (disease causing) mechanism and developing treatments, remains something which is being actively pursued in many large centres around the world (including the centres providing the NHS Rare Mitochondrial Disorders Service).

Diagnostic Strategies

If you or your child is suspected of having Mitochondrial Disease the doctors will undertake a number of investigations. These will determine the nature and also the extent of the Mitochondrial Disease.

Blood and urine samples

Blood samples are very useful to investigate whether or not patients have a high level of lactate (a bi-product of faulty mitochondria). However, lactate levels can vary substantially, particularly if the sample was difficult to obtain, and many patients with Mitochondrial Disease can have normal blood lactate. Some doctors look for other metabolites such as alanine, in blood and occasionally urine. On the whole, whilst these metabolites give important clues as to the presence of Mitochondrial Disease they are by no means specific.

Blood might also be used to detect genetic changes or faults. In patients suspected of having a well known genetic change, blood is a very useful tissue to investigate for some but not all Mitochondrial Disorders. Certainly, common mitochondrial DNA changes associated with well described and well known Mitochondrial Diseases such as Leber’s hereditary optic neuropathy and MERRF can be detected easily in blood, and this is the tissue which most centres would investigate. Nuclear genetic disorders can also be detected in blood and again a blood sample would remain the tissue of preference to investigate patients with suspected nuclear genetic Mitochondrial Disease.

Urine samples are very helpful for the investigation of the 3243A>G MELAS mitochondrial DNA change. The reason for this is that 3243A>G might be at quite low levels in blood and therefore difficult to detect, where as in urine it is usually present at a much higher level.

Lumbar Puncture

The brain and spinal cord sit in a fluid called cerebrospinal fluid. Sampling of this fluid by lumbar puncture can be useful in the diagnosis of Mitochondrial Disease, particularly in children. As this fluid surrounds the brain, its composition gives important clues as to how the brain is functioning. A lumbar puncture involves placing a small needle under local anaesthetic into the small of the back in order to collect a very small volume of this fluid. A lumbar puncture test is usually only done in the investigation of Mitochondrial Disease in children. A lumbar puncture test is helpful in distinguishing Mitochondrial Disease from other diseases and can allow detection of high levels of lactate in the cerebrospinal fluid, which surrounds the brain and spinal cord. Lactate is produced if mitochondria are not working well and in some patients, high lactate levels are seen only in the cerebrospinal fluid and not in the blood. Thus it is a valuable test in children who predominantly have neurological problems.

Muscle Biopsy

For many patients with Mitochondrial Disease, doctors recommend a muscle biopsy. Muscle is in fact a very good tissue to investigate because it is commonly affected in Mitochondrial Disease and several tests can be done on the muscle biopsy that are extremely helpful. It is certainly possible to look at the distribution of mitochondria on a muscle biopsy and actually to measure the activity of certain enzymes crucial to mitochondrial function. In both children and adults, this may be extremely helpful in finding whether or not a mitochondrial defect is present and also understanding the nature of the mitochondrial problem. These muscle biopsies are taken and may be processed fresh, or more often frozen, in specialised centres (including the centres providing the NHS Rare Mitochondrial Disorders Service). In children, defining whether or not there is a biochemical defect can be extremely helpful in determining whether Mitochondrial Disease is present. Indeed it may be the only abnormality that we are able to detect.

The muscle biopsy is also very helpful in terms of genetic analysis for Mitochondrial DNA Diseases. Mitochondrial DNA changes or faults might only be present at high levels in muscle and thus detecting the abnormality can be much easier in a muscle biopsy than in a blood sample. For example, deletions (where a bit of mitochondrial DNA is missing) or rare 'spelling mistakes' (where only a single base is changed in the 16,500 base pair genome) might only be detectable in muscle. Therefore, the extensive genetic investigations that are performed are often better done in muscle biopsies rather than in blood samples.


In many patients there is disturbance of brain function associated with Mitochondrial Disease. This disturbance of brain function is picked up clinically, but working out which bits of the brain are affected is often helped by taking pictures (or images) of the brain. There are two main modes of imaging, one is using a CT scan, which is like a sophisticated x-ray and the other is using magnetic resonance imaging (MRI scan). On the whole, a MRI scan gives much more information, but is more difficult to perform since it usually takes at least 20 minutes (much longer than in a CT scan) to obtain good quality images of the brain. These images can be extremely helpful in working out whether patients have Mitochondrial Disease and also the severity of the disease.

Clinical guidelines on genetic testing

Best practice guidelines for professionals on genetic testing for mitochondrial diseases have been published by the NHS Highly Specialised Service for Rare Mitochondrial Disorders, and can be found be clicking here