ME/CFS and mitochondrial disease

In diagnosing and attempting to treat Chronic Fatigue Syndrome the physician is faced with a plethora of possible causes. These include chronic viral infections, gut infections, and exposure to pathological moulds (such as Aspergillus) or toxic chemicals (such as agricultural sprays) in the environment. But alternative diagnoses must also include the rare but devastating 'Inherited Metabolic Diseases', particularly the ones that affect the 'Mitochondria'.

Mitochondria and energy

We inherit differing eye, hair and skin colours from our parents - and these arise from differences in the biochemistry or metabolism of eye and skin pigments that we inherit from our parents. An important aspect of our metabolism includes our mitochondria: these are the 'energy factories' of cells throughout the body. Disorders affecting mitochondria can be either inherited or acquired. Mitochondrial disease and a resultant “chronic fatigue” type syndrome can be acquired from exposure to various environmental pollutants (for example, chronic exposure to organophosphate insecticide sprays). Inherited mitochondrial disease often runs in the female side of the family, but not always. Whatever the cause, mitochondrial disease can be difficult to diagnose. This is partly because, from the doctor's point of view, mitochondrial disease can be perplexing: it can affect many the parts of the body, with the common characteristic that the affected organs are particularly energy-dependent:

• muscles (lost power- skeletal/heart/gastric)
• brain and nerves (loss of sensation and control)
• eyes (drooping eyelids, loss of eye movement, retinal blindness)
• digestive system (poor bowel function, leading to obstruction)
• exercise fatigue and loss of muscle power
• weight loss
• loss of muscle mass
• diabetes.

How are mitochondrial disorders diagnosed?

1. Look for a mutation in the gene (genetic diagnosis). This is relatively simple if a mutation is known. But there is a complication with mitochondria. The cells that form your body are made under the instructions of your genes (DNA) in the nucleus of each cell. But the mitochondria in those cells are different: they are constructed partly from DNA from the nucleus and partly from their own mitochondrial DNA. This makes genetic analysis complicated.

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2. Measure the activity of the mitochondrial protein (enzyme) that is thought to be affected. This has its own problems, because it needs prior knowledge (or a good guess) of what protein function has gone wrong. Because there is usually only a small amount of tissue sample available, the laboratory usually only gets one chance to choose the right protein analysis.

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3. Examine a piece of affected tissue (for example, muscle) using a microscope. This can be used to look for damage indicating mitochondrial disease, for example, 'ragged red fibres' can be seen in muscle by light microscope, and abnormal mitochondria can be seen by electron microscope. This doesn't usually tell the doctor what is actually wrong - it only confirms that mitochondria are implicated.

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4. In some cases, changes in the chemistry of mitochondria caused by a disorder can be spotted by changes in the body's chemistry. For example, the mitochondrial disorders often (but not always) cause an abnormal build up of a chemical, lactic acid, in cells. This can leak out into the bloodstream and can even be detected in urine.

There are two serious difficulties with diagnosing mitochondrial disorders:

(a) A phenomenon known as 'heteroplasmy'. This refers to the fact that mitochondria are not necessarily the same all through the body. For example, a leg muscle may have some cells with damaged mitochondria and normal normal cells. Even within a single cell, there may be some normal and some diseased mitochondria. This makes it difficult for a hospital laboratory to rely on a sample of mitochondrial DNA or protein as representing the patient's condition elsewhere in the body.

(b) Diagnostic testing requires a 'biopsy', that is, a piece of the affected tissue. Taking a biopsy can be unpleasant and hazardous, so doctors are generally reluctant to do so unless they have a strong suspicion of a mitochondrial disorder. Even then, the biopsy suffers the problem of heteroplasmy - the piece of tissue may be from healthy tissue surrounding the affected tissue.

MNGIE: an example of a mitochondrial disease

MNGIE stands for 'mitochondrial neurogastrointestinal encephalopathy.' Its name implies it primarily affects nerve cells (neurones), the gastric and intestinal system, and the brain. It is characterised by loss of eye muscle control, drooping eyelids, limb weakness and cramps, and digestive problems including chronic diarrhoea or constipation and abdominal pain. 'Borborygmi' (loudly grumbling bowels) seems a common feature early in life. It is a serious mitochondrial disorder and usually culminates in severe bowel obstruction and death in the early 20's. Fortunately it is rare and may represent only a small fraction of chronic fatigue and mitochondrial disease.

MNGIE is diagnosed fairly easily and unambiguously by measuring accumulation of two abnormal chemicals - deoxyuridine and thymidine - in urine or blood, plus other chemical (metabolic) clues. In Australia the test is presently available at the Pathology Department of the Brisbane Mater Hospital as well as other Australian capital cities.

In conclusion, there seem to be big advances coming (finally!) in understanding ME/CFS, using powerful new genetic techniques such as 'microarray' analysis. These new results are pointing primarily towards two aspects: the body's ability to fight infection, and mitochondria function. But for diagnosing ME/CFS, we need first to carefully exclude other genetic and metabolic disorders such as MNGIE or other mitochondrial diseases. Failure to distinguish patients with other diseases from ME/CFS will decrease the power of any future genetic studies and slow progress of future research aimed at explaining ME/CFS.

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