Mitochondrial Disease Information

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 200 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’

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).

Since the high energy organs require so many mitochondria within their cells, they are usually the first to be affected by mitochondrial disease. These include the brain (using 20% of our total energy), nerves, muscles, eyes, ears, heart, bowels, liver, kidney and pancreas. The red cells in our blood are the only cells in our body that lack mitochondria. However, they can also be affected by mitochondrial disease since the bone marrow stem cells they come from need mitochondria to produce the haemoglobin that carries oxygen around the bloodstream.

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) is due to a change in one or more of the genes that make up the mitochondria. This means a fault will occur in either the production or function 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 mito can strike each person.

Mitochondrial disease (mito) 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 effect on body functioning. So far we know of at least 350 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).

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:

• a ‘common disease’ has atypical features; and/or
• three or more organ systems are involved; and/or
• 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.

Mitochondrial Disease DiagramThe 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 the complexity of mitochondrial genetics, 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.

As mentioned earlier, mitochondrial disease is often referred to as the ‘notorious masquerader’. Therefore, other illnesses are usually investigated long before mitochondrial disease is considered. This means that people with mitochondrial disease are often ‘hidden’ in other areas of medicine and this creates frustration and confusion for patients, practitioners and specialists.

Given its elusive nature, mitochondrial disease should be considered in all patients with an atypical presentation, particularly those suggested in the diagram below.

Also, some overlap is beginning to emerge with mainstream illnesses, for example, there is strong evidence that impaired mitochondrial function is important in Parkinson’s disease, diabetes and diabetic complications. Disorders such as Alzheimer’s, autism, cardiovascular disease and some forms of cancer have also been associated with mitochondrial dysfunction, as has the process of ageing.

Mitochondrial disease can be classified as primary or secondary. Generally, when we talk of mitochondrial diseases, we are usually talking about the primary type. That is, the type caused by a change in the genes used to make the mitochondria.

The secondary type is always related to another illness, an illness that has caused the mitochondria to malfunction despite the normal formation of mitochondria initially.

Primary mitochondrial diseases are therefore genetic disorders and may present in a number of different ways:

1. there is a clear family history of the known mitochondrial disease
2. there is a family history of peculiar, undiagnosed illnesses that could be mitochondrial disease
3. family members appear well and healthy but are unknowingly carrying the genetic defect which is passed onto their children, or
4. mitochondrial genes are mutated for the first time in an individual who may become unwell themselves or possibly pass it onto their children who become unwell later.

Therefore, due to the broad range of presentations and genetic defects of this illness, it can originate at any point in time.

In summary, frequently it is carried down only on the mother’s side (see diagram below), infrequently only on the father’s side, it may have required both parents for it to be carried down, or it may be mutated for the first time.

Due to the elusive 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 200 people will carry a mitochondrial genetic defect – that equates to more than 120,000 Australians.

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.

The prognosis and pathway for any mitochondrial patient is hard to predict as it is an illness that can strike many parts of the body to varying degrees.

As mentioned earlier, combinations of symptoms differ greatly even in those with exactly the same genetic defect.

Therefore, no single rule applies to any patient or subgroup.

Individual prognoses are best discussed with your own doctor.

For children to develop the illness, it means they have a high load of abnormal mitochondria. Hence, the illness tends to progress more quickly than in adults and with a poorer prognosis. The older a person is when symptoms occur, the slower the progression and the better the prognosis. People who develop symptoms late in life are often not diagnosed at all and will pass away from other unrelated illnesses.

Individual symptoms will cause corresponding disability with progression of the illness. Poor mobility, poor coordination, weakness and fatigue can sometimes create a need for a walking frame or a wheelchair. Hearing loss is often helped by hearing aids or a cochlear implant in severe cases. Some visual symptoms may be alleviated by surgery but complete/ incomplete blindness will require visual aids.

Some patients find they need the help of a carer or some home-help. The local hospital can often provide appropriate services by allied health professionals. A health professional such as a social worker, occupational therapist, speech therapist, and physiotherapist, with their access to a variety of equipment, home aids and services, can help the mitochondrial patient cope better with daily life.

Unfortunately, at the moment there is no cure. There is also no single treatment for mitochondrial disease and treatment will need to be tailored for each individual. However, appropriate lifestyle changes are an effective treatment.

The general principals rely on the ‘energy balance equation’, that is, to minimise energy losses and to optimise energy gains. This reduces stress on the mitochondria and creates the optimal environment for the mitochondria to function.

The best way to manage ‘energy loss’ is to have adequate rest and to avoid physical stresses such as infections and big temperature changes, as well as emotional stresses.

Optimising ‘energy in’ will require adequate sleep and nutrition, and a balanced and regular exercise program.

To optimise the mitochondrial environment, we often use what is called a ‘mitochondrial cocktail’ which involves a variety of vitamin and cofactor supplementation. There is no ‘standard’ cocktail.

Regular visits to a specialist will monitor any progression or changes in the illness and if found early enough, each complication or development can be better managed.

Many patients in earlier days were diagnosed with ‘mitochondrial myopathy’ and were sent home without treatment or support. Now we know a great deal more and the appropriate management of the illness may not only improve the prognosis of the individual, it can also greatly improve their quality of life.

Doing nothing can worsen the symptoms, increase the level of disability, decrease independency and worsen the prognosis.

Because mitochondrial disease is often ‘invisible’, the biggest challenge the patient faces is convincing the doctor there is something wrong. There is a medical void that currently exists regarding this illness, partly due to the illusive nature of the illness and partly due to it being relatively new.

If a diagnosis is not established it can be difficult for a patient to obtain adequate medical care, healthcare supports and disability services. This can contribute to a progression of symptoms and a risk of inappropriate treatments and management.

Mitochondrial disease affects not only the person with the illness but carers and family as well. So carers and family may even be in need of their own support, support they might have to continuously fight for given the poor education about this disease.

Mitochondrial disease can be unpredictable, day to day and hour to hour. On good days a person with the illness can appear normal so its severity is often doubted. On bad days the person can be extremely ill, making it difficult to return to the original baseline.

Mitochondrial symptoms are very often atypical and bizarre and challenge even the best specialist to ‘think outside of the box’. Standard medical tests may not give a complete picture of what is actually happening.

All of these factors can make it difficult to get through a ‘normal day’. The Mito Foundation is currently building a collection of resources, including articles, lifestyle advice and details on community and allied health services that can assist people with these daily challenges, big and small.
“An observant parent’s evidence may be disproved but should never be ignored”

The Mito Foundation aims to:

• unite people with mitochondrial disease and their families
• provide accurate and useful information and advice
• set up support groups for the mito community
• represent the mito community at government level
• provide an urgent medical help line
• advise on or provide access to medical or associated health services