Our body is made of cells, each one being specific to the part it belongs to: muscle cells make up muscles; brain cells make up the brain; and so on. Each cell is a life-form in itself. Imagine a cell being like an egg: it has a centre called the nucleus which acts like the ‘brain’ of the cell, controlling nearly all its functions; and a cytoplasm (a bit like the egg white) which contains many tiny structures that help the cell to survive.

Some of the structures in the cytoplasm include lysosomes that help break up the cell's waste and debris, the cytoskeleton that helps the cell to maintain its shape, and of course the mitochondria, the batteries of the cell that provide its energy.

 

The mitochondria's job is to take in energy from the food we eat, such as fats and carbohydrates, and then like a refinery (turning crude oil into pure petroleum) turn those substances into ATP. This ATP is the cell's pure energy and it is used to power the nucleus and hence control the cell.

 

Mitochondria are extremely complex, and just like the oil refinery they require many things to make them work such as vitamins and coenzyme Q10. They also produce their own waste, such as ‘free radicals’.

Like the small light that hangs off a key-ring, or the huge emergency torch that saves us in a blackout, each organ requires different amounts of energy.

 

Hence, high energy organs that do a lot of work, such as the brain, contain cells with 1,000s of mitochondria (like the many batteries in the large torch). The low energy organs might only contain a few mitochondria in their cells, such as the platelets in our blood (like the single battery in the small torch). The red blood cell is in fact the only cell in our body that requires no energy and hence has no mitochondria....its main purpose is simply to carry oxygen.

 

Since the high energy organs require so many mitochondria within their cells, they are usually the first to be affected in mitochondrial disease. These include the brain (using 20% of our total energy), nerves, muscles, eyes, ears, heart, bowels, liver, kidney and pancreas.

Mitochondria are extremely complex little organelles and each one requires over 1,400 genes to create it. Our genes are like the blueprints of our body, dictating exactly how we will be made and how we function.

Mitochondrial disease (‘mito disease’ for short) is due to a fault in one or more of the genes that make up the mitochondria. This means a hiccup will occur in the production of mitochondria from the time of conception. As the foetus grows, some mitochondria can divide and grow as normal whilst others will divide and grow abnormally.

 

The ratio of healthy to unhealthy mitochondria can also vary greatly from cell to cell and organ to organ. This is the main reason why it is so difficult to know where and when and how severely mitochondrial disease can strike each person.

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Until about five years ago, mitochondrial disease (the name, not the disease), did not seem to exist. It is an illness that seems to have suddenly appeared and one that most GPs don’t know about. Therefore, it’s easy to think that it must be rare, unimportant, or even not serious.

 

However, type ‘Mitochondrial Disease’ into Google and faces appear of people who have it, many are children. Although medicine continues to advance rapidly, why is this illness not being considered, and why do most sufferers remain undiagnosed or misdiagnosed?

 

Many experts refer to mitochondrial disease as the ‘notorious masquerader’ because it mimics so many different illnesses, affecting both children and adults. Due to its widespread variety and severity of symptoms, diagnosing mitochondrial disease can be extremely difficult.

 

Recent research demonstrates that mitochondrial mutations are present in at least 1 in 250 people and that at least 1 in 5,000 will develop serious illness. So here’s how we summarise mitochondrial disease…

 

‘…any organ, any symptom, any age’

Mitochondrial disease can have many presentations because mitochondria are located everywhere within the body. The severity of damage, location, and number of mitochondria affected all have an affect on body functioning. So far we know of at least 100 different types of mitochondrial disease with the potential for 100s more. New presentations of this disease appear regularly.

 

Some mitochondrial disorders might only affect a single organ, such as the eye in Leber hereditary optic neuropathy (LHON), but most involve multiple organs, with the nerves and muscles being affected the most.

 

Many affected individuals will present with a number of features that fall into a discrete subgroup, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibres (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS).

 

Others subgroups may be named according to the actual defect occurring in the mitochondria, such as COX deficiency or complex I and IV deficiency. However, many individuals will not fit neatly into any one particular subgroup. Also, the actual genetic hiccup will not be found in many cases.

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When we think of the symptoms that might present in mitochondrial disease, we need to think of the organ systems that work the hardest and the longest and so require the most energy. Also, the complex specialisation of mitochondria within each cell causes a dizzying array of symptoms that mitochondrial specialists have come to recognise as characteristic of this illness.

 

Symptoms may be absent in healthy people who have silent genetic defects, or can be complex and multiple in a person with advanced disease. Many combinations of symptoms are also possible, even in those people with exactly the same genetic defect!

 

Therefore, with so many illnesses looking like mitochondrial disease and mitochondrial disease looking like so many illnesses, how do we know which is which?

 

Firstly, we must suspect mitochondrial disease when:

1. a 'common diseas' has atypical features; and/or

2. three or more organ systems are involved; and/or

3. recurrent setbacks or flare-ups occur with infections in a ‘normal’ chronic illness.

 

The most common symptom is fatigue. This is not the type of fatigue one experiences after a busy day. Rather it feels like ‘hitting the wall’. Often when mitochondria are well rested, a person can achieve what they want and appear ‘normal’. However, in times of excess energy loss, high physical stresses or poor energy input, the person may feel extremely fatigued and often struggles to simply get out of bed.

 

These energy level fluctuations can make it difficult for a person to present their case to a practitioner. Overall, like most mitochondrial symptoms, the fatigue will progress over time, although at vastly different rates for different people.

 

The highest energy user in our body is our brain. The brain works constantly in the background, monitoring and controlling most of our bodily functions to the point where it requires 20% of our total energy input. The main neurological symptoms of mitochondrial disease include developmental delays, mental retardation or regression, dementia, seizures (especially atypical or refractory ones), coma, neuro-psychiatric disturbances, atypical cerebral palsy, myoclonus (brief, involuntary muscle twitching), movement disorders, ataxia (poor coordination), migraines and strokes.

 

Symptoms relating to muscles and nerves include weakness (may be intermittent), altered nerve sensation, fainting, temperature regulation problems, low muscle tone, muscle cramping or pain, and recurrent rhabdomyolysis (rapid muscle breakdown).

 

As our ears and eyes rarely rest, visual loss or blindness, and deafness (often intermittent) are another common feature of mitochondrial disease. Weak eye muscles may present as droopy eyelids (ptosis), and difficulty in moving the eyes together. Night blindness and colour-vision deficits are other less common but possible symptoms.

 

The bowel can show symptoms such as gastro-oesophageal reflux (indigestion), delayed gastric emptying (feeling full a lot), constipation, pseudo-obstruction, chronic or recurrent vomiting, and sometimes difficulties in swallowing. Unfortunately, these complaints are common so it is hard to determine their cause.

 

The kidney, heart and liver are often the forgotten high energy organs, but are very significant because their deterioration plays vital roles in the patient's prognosis. Nephrotic syndrome, the loss of important electrolytes in ‘leaky kidneys’, heart arrhythmias, heart blocks, cardiomyopathy (large heart), and unexplained liver abnormalities are some of the earlier signs that could lead to the events of kidney, heart or liver failure.

 

Diabetes, short stature, an underactive thyroid or parathyroid, excess body hair, exercise intolerance not in proportion to weakness, hypersensitivity to general anaesthetics, and symmetrical fatty lumps in the skin are other symptoms to alert someone of possible mitochondrial disease.

 

In children, symptoms such as IUGR (poor growth inside the womb), unexplained low muscle tone, weakness, failure to thrive, infantile spasms, unexplained seizures/fits, microencephaly, and a family history of SIDS should be investigated further, especially if the child does not progress or seems to be slowly deteriorating.

 

The diagram on the right shows a summary of possible mitochondrial symptoms. Over time as we study and further understand this illusive illness, we will be better equipped to diagnose it.

To prove the existence of mitochondrial disease in a newly presenting patient is a bit like doing a jigsaw puzzle. The collection of pieces and putting them into place begins with the family doctor and progresses to the mitochondrial specialist. After considering the possibility of mitochondrial disease it’s then a matter of putting the pieces on the table and turning them up the right way to see them all together!
 
Mitochondrial disease is a multi-system illness, so a thorough history and examination of all the organs mentioned above can be done by a GP. General questions about fatigue, muscles, nerve problems, intellectual/mental issues, hearing, sight, bowel/heart/liver/kidney problems, or diabetes are a good place to start. A family history of similar illnesses or symptoms is important, especially if the illness was atypical (e.g., atypical MS) or a death was unexplained. Because mitochondrial disease is relatively ‘new’ it is unlikely that there will be a clear and distinct family history of the illness.

 

Basic investigations such as hearing tests, eye tests, blood tests, etc., can be done straight away. The next and more specialised investigations are best done by a mitochondrial specialist or a neurologist with knowledge of the illness, or in the case of children, a metabolic geneticist.

 

Individual systems/organs can then be tested more thoroughly along with non-specific mitochondrial function tests using blood, urine, hair, skin cells or tissue biopsies etc. Results from the classical muscle biopsy may be misleading so a number of different tissues are now being used as samples.

A fairly clear picture of the puzzle should now be emerging. If not, then a six-monthly or yearly review can reveal more pieces.

 

The FINAL piece of the jigsaw puzzle would be a positive genetic test. Unfortunately, due to 1,400 genes making up a single mitochondrion and our ability to test only one at a time, this is often unlikely, especially in the lesser known genetic mutations of mitochondrial disease. Mitochondrial disease can therefore become a clinical diagnosis (that is, a diagnosis based on symptoms and signs and basic investigations) in the hands of the right specialist.

Due to the illusive nature of the illness, it is difficult to know the exact incidence of mitochondrial disease. Worldwide statistics have varied considerably over time, but conservatively, from recent Australian studies, about 1 in 250 people will carry a mitochondrial genetic defect.

 

Not all of these people will develop the illness, and many may develop subtle symptoms that go unnoticed during their lifetime... BUT the risk of developing serious illness in the general population is about 1 in 5,000. As we study the illness more and diagnose it better that incidence will rise.

Mitochondrial disease is one of the most rapidly growing areas of interest in the world of research. Not just because of the illness itself, but the mitochondria has now been shown to play vital roles in many other illnesses. 

 

Mitochondrial dysfunction has been implicated in disorders such as copper-metabolism disorders (Wilson disease and Menkes disease), some lysosomal disorders, neonatal haemochromatosis, malnourished children, (with correction to normal levels after improved nutrition), cancer, Parkinson's disease, Alzheimer's, and heart disease. A lifetime of mitochondrial damage may also be part of the aging process.

 

1. Research is therefore vital and is one of the main aims of the world mitochondrial community. The organisations participating in World Stay in Bed Day support a number of projects through the provision of scholarships and research grants. These projects deal with a variety of aspects such as diagnostic and treatment dilemmas.