Questions & Answers

Our Q&A section has been written by the charity and reviewed by members of our expert medical board. The information provided is general advice to help improve the understanding of Mitochondrial Disease. The information is for purely educational purposes. The charity does not warrant that the information we provide will meet your health or medical requirements. It does not constitute medical advice and the charity is not liable should it be treated as medical advice. Every patient with Mitochondrial Disease is different and if you have any concerns about you or your child's health you should seek direct medical advice from a specialist medical practitioner.

 

1. What are mitochondria & what do they do?

Mitochondria are tiny structures found in almost every cell in our bodies.  They convert the food we eat into the energy we need to survive and grow.

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2. How many mitochondria are in our cells?

The number of mitochondria in each cell can vary between one and many thousand, depending on how much energy that cell needs.

Busy cells like brain, heart or liver cells need a lot of energy to function properly and therefore have lots of mitochondria.

Actually the number of mitochondria in an individual cell is continually changing because they fuse with each other and divide on a regular basis.

There is also variation from cell to cell in the same tissue and between different individuals.

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3. Mitochondrial DNA and Nuclear DNA – what is the difference?

Many people don't realise that we all actually have 2 different types of DNA in our bodies. Most people are familiar with nuclear DNA which looks like a twisting ladder and makes up 99.9% of the total DNA in our bodies. It is responsible for determining all the unique characteristics that make us who we are.

Slightly less familiar, is mitochondrial DNA which is a tiny ring shaped structure. It plays no part in determining our unique characteristics but it is crucial for the production of our energy. 

Our nuclear DNA contains over 20,000 genes whereas our mitochondrial DNA only contains 37 - although it is small, we couldn't live without it!

Nuclear DNA 

Nuclear DNA is found within the nucleus of our cells. It is linear in shape and it makes up 99.9% of the total DNA in our body. 

ndna_theo.jpeg

Within the cell, the Nuclear DNA is packaged up into structures called chromosomes. Humans have 46 chromosomes per cell which are arranged in pairs (23 of these come from your mother and 23 from your father). These chromosomes contain between 20,000-25,000 genes.

Nuclear DNA (and the genes that it holds) are responsible for providing the basis for how human bodies are built and work, as well as determining all our characteristics.

Mitochondrial DNA 


mdna_theo.jpegThis is a special circular type of DNA that is only found within the mitochondria themselves and it makes up only 0.1% of the total DNA in our bodies.

Mitochondrial DNA contains only 37 genes, all of which are essential for normal mitochondrial function (13 of these genes provide instructions for making enzymes involved in the Electron Transport Chain and the remaining genes provide instructions for making molecules which help put proteins together.)

Mitochondrial DNA is inherited only from your mother (as the fathers mDNA is destroyed during fertilization). Humans contain between 100-1000's copies of mitochondrial DNA per cell.

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4. What is Mitochondrial Disease?

Mitochondrial Disease occurs when our Mitochondria are not able to provide the energy our cells need to work properly.

Without the right amount of energy, our cell's cannot do their job  and they stop performing and start to die.

If a lot of Mitochondria in the body are affected, especially in important body organs, Mitochondrial Disease can be very serious and often fatal.

Each affected individual will have different symptoms and severity of the condition because a different combination of their Mitochondria are working and not working within each cell, and each person might also have different cells in the body affected.

Mitochondrial Disease is not a single disease but more like a collection of conditions. The underlying genetic cause may be different for different people but all will result in the inability of the mitochondria to produce the right amount of energy which causes this disease.

Some types of Mitochondrial Disease affect only one organ and some affect multiple organs.

There are times when particular organs or body systems are affected in a recognisable pattern and these have been given 'syndrome names' like for example Alper’s, Leigh’s disease, MELAS or MERRF to name only a few.  More about these recognised patterns can be found by clicking here (link)

Mitochondrial Disease might also be classified by the specific complex of the respiratory chain that they affect eg Complex I.

Also Mitochondrial Disease may be classified by the specific gene mutation that has caused it.

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5. Is Mitochondrial Disease a metabolic disorder?

Yes it is.

A metabolic disorder simply means that one of the processes by which your body makes, uses or disposes of certain materials is abnormal.

Mitochondria perform many metabolic tasks but ‘Mitochondrial Disease’ refers specifically to problems with the task of converting energy from one form into another using the specialized machinery within the mitochondria.

There are also many metabolic disorders that do not affect this process of energy conversion even though they might be occurring within the mitochondria. (an example would be a Urea Cycle Disorder – the process occurs inside the mitochondria, but these  disorders are not considered Mitochondrial Disease but are metabolic disorders.)

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6. Why does Mitochondrial Disease occur?

Mitochondrial Disease occurs when our mitochondria are not able to provide the energy our bodies need.

This is usually the result of a genetic defect which disrupts energy production and is present at birth. This defect can either be in either our mitochondrial DNA or in our nuclear DNA.

7. How common is Mitochondrial Disease?

The true prevalence is very difficult to determine due to the wide range and varying severity of the symptoms experienced. This means it is often overlooked or misdiagnosed. In addition, the range of genetic mutations that can cause the disorder is vast which makes genetic diagnosis a challenge.

It is believed that 1 in 200 babies in the UK are born with genetic changes that can cause mitochondrial disease although there are no official statistics that record the number of children that go on from this to develop serious disease.

The incidence of mitochondrial disease in the adult population is estimated at around 1 in 4,300 (Gorman et al. Annals of Neurology 2015) and as we learn more about Mitochondrial Disease and as diagnostic tools improve we are likely to see a significant increase in diagnosed cases.

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8. Does it affect boys and girls equally?

Yes - the vast majority of Mitochondrial Disorders affect boys and girls equally.

There is a very small sub-group of mitochondrial disorders that may have a more serious onset in boys than girls because of the way they are inherited. These are known as x-linked disorders and include Pyruvate Dehydrogenase Deficiency (PDHD).

9. Does it affect one particular ethnic group more than others?

It is believed that Mitochondrial Disease affects all ethnic groups equally although we are not sure that any specific research has been done in this area.

On paper, prevalence may appear higher in the developed world but this is likely to be due to the more advanced healthcare and diagnostic tests available and better record keeping.

10. Can it affect both adults and children?

Yes, but the disease often has different characteristics depending on the age of onset.

Childhood disease is usually more severe due to the nature of the mutations that have been inherited and is often life limiting.

With adult disease, symptoms may accumulate over time and may be masked by other more common diseases of ageing.

In terms of population prevalence, adult onset disease is actually much more common than childhood disease, partly because childhood onset disease is often fatal at a very early age whereas adults often survive for many years after the diagnosis is made.

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11. How do you get it?

You cannot catch Mitochondrial Disease, you are born with it. Mitochondrial Disease is caused by genetic mistakes (mutations in our genes).

Mitochondrial Disease can be inherited, but the way this can happen is extremely complicated. It can be from the mother or father or both. It is also possible that the mistake may have arisen for the first time in the affected person.

I want to know more 

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12. What are the symptoms?

Lack of energy is a common outward symptom of Mitochondrial Disease but inside the body it's much more serious and complex. Mitochondrial Disease may literally cause any symptom, in any organ, with any degree of severity, at any age.

Children typically present with failure to thrive, motor regression, encephalopathy, seizures, swallowing problems and breathing difficulties like apnoea (long pauses in breathing pattern).

In contrast, Adults frequently develop hearing loss, muscle weakness, diabetes, gastrointestinal dysmotilty and fatigue.

Symptoms of Mitochondrial Disease vary hugely depending on the actual mitochondrial syndrome or underlying genetic mutation that has caused it.

I want to know more

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13. How do you diagnose Mitochondrial Disease?

The diagnosis of Mitochondrial Disease often involves a long and complex journey for both patient and doctor.

Blood tests, spinal fluid tests, muscle biopsies and MRI scans are all useful tools which can indicate when our mitochondrial are not working as they should, however 'normal' results from these tests do not always rule out Mitochondrial Disease.

Genetic Testing using next generation sequencing is becoming increasingly popular but is only available to patients through research projects and is not yet available on the NHS. We are proud to fund this testing at a number of UK centers.

We are hearing how important it is for doctors to look closely at the clinical picture - listening to and observing all the patients symptoms (which may initially appear unrelated) and taking a detailed family history can often be the key to putting the pieces of this complex condition together.

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14. Why does it take so long to diagnose?

Mitochondrial Disease is very rare. With symptoms of the disease beginning at any age and affecting any body system in ways that are not clearly linked, you can see why it is particularly challenging to diagnose.

Many symptoms are common to other diseases and these need to be ruled out before the diagnosis of Mitochondrial Disease is arrived at.

In addition there are lots of different genes involved in healthy mitochondrial function, any one of which could go wrong and cause disease, so finding the underlying defect through genetic testing is key, but also time consuming.

Once a doctor suspects Mitochondrial Disease based on symptoms of the patient, there are a number of tests that must be undertaken to try and confirm this diagnosis which again takes time. You can read about these in the question above.

15. Are there different severities of Mitochondrial Disease?

The severity of the disease ultimately depends on the underlying genetic cause. With maternally inherited Mitochondrial Disease, a person may have a certain percentage of their mitochondria not working.

If it is a small %, their symptoms may be mild or not begin until later in life. If it is a large % then symptoms often begin in early childhood and can be severe and often life limiting.

This is not the case with most nuclear DNA mutations where severity is much more closely linked to the specific genetic mistake (mutation). As a rule, autosomal recessive nuclear DNA mutations with early onset are the most severe. Autosomal dominant disease such as AD POLG / AD Twinkle / AD RRM2B etc tend to have a later onset.

There are also circumstances where the severity is organ dependent eg the Brain in Leigh Syndrome. The involvement of such a key organ makes this a very severe form of Mitochondrial Disease with knock on effects to many other organs. In addition the involvement of the Liver in Alpers, causes acute liver failure in many patients.

16. What is the difference between complex 1,2,3 4 diseases - is one worse than the other?

The various numbers refer to the various processes involved in energy production (the electron transport chain) in the mitochondria. A higher number is not worse - it just helps doctors explain which part of the mitochondria might not be working well and help direct treatment or genetic testing.

Because these mitochondrial components live alongside each other, by having one portion not work properly - another portion may also not work as intended - so a person can have more than one complex affected.

17. Does Mitochondrial Disease worsen / progress with time, or can it improve?

Mitochondrial Disease is a progressive condition which means that it will get worse over time.

The rate of progression however varies hugely from patient to patient and is dependent on a number of factors including the underlying genetic defect, the organs affected by disease and exposure to infection/medical or physiological stress.

Some patients have chronic symptoms that remain stable for a number of years and others may have a slow steady or rapid downhill progression.

There is also a very small group of patients who appear to have a reversible form of mitochondrial disease that begins in infancy and improves with time if sufficient medical support is provided initially. The mechanisms causing these reversible forms of mitochondrial disease have not yet been fully elucidated but mutations in the TRMU gene or the mitochondrial DNA point mutation m.14674T>C seem to be important.

Every patient is different.

18. Do Vaccines cause or worsen MD?

There is no clear evidence that immunisations themselves hurt mitochondria or mitochondrial disease patients.

Medical stress (fever, dehydration, illness, revving up the immune-system) may bring-out or worsen metabolic disorders. Thus, there have been some patients where the fever after an immunization led to symptom onset or worsening. In these individuals - it was not directly the immunization that led to issues.

Doctors recommend that patients receive immunisations. If they are sensitive to declining during medical stress - spacing out immunizations and tight fever-control may help (but this type of approach is not based on medical science and what physicians call 'anecdotal experience').

19. Does Mitochondrial Disease affect the immune system?

This topic is still actively being studied and at present there is no evidence to link mitochondrial dysfunction with increased rate of infection or indeed immunodeficiency.

We know that having mitochondrial dysfunction leads to more chronic non-life-threatening infections (colds, ear-infections) - and in some patients - having these medical stressors recur frequently leads to a decrease in quality of life. This is more likely to be because shrugging off these type of infections might be more difficult for the patient with Mitochondrial Disease, probably as a result of the impact on their other organ systems.

There is one condition Cartilage Hair Hypoplasia where a link with mitochondria has been established.

20. Are there any medications that I should avoid?

Following are some medications that have been flagged as having contraindications in some patients with mitochondrial disease. However it is unwise to stop any prescribed medications abruptly.

If you are concerned about the medications you are taking, then you should discuss this with your doctor at the earliest opportunity.

21. What Treatments are currently available?

Even though mitochondrial disorders are currently incurable, certain interventions may be helpful in reducing the impact of the condition and limiting further disability.

Supplements may be helpful in slowing the progression of the disease and medications or assistive devices may be useful in reducing specific symptoms.

Dietary alterations may improve wellbeing and making lifestyle changes, such as taking moderate exercise, could actually improve mitochondrial health.

Read more

22. Are there any Treatments in development?

A new wave of experimental drugs are currently in development, which aim to prevent or reverse some of the main symptoms of mitochondrial disease.

Read more

23. What is the Prognosis?

In general, Mitochondrial Diseases are progressive diseases and a substantial number of children with Mitochondrial Disease do not reach adulthood. 

The rate of progression can be variable and unpredictable but most patients will eventually develop involvement of several organs. When there is cardiac involvement, brain involvement or stoke like episodes the disease tends to be more severe but every case is different.

Although there are currently no real treatments or a cure at present, there is now money being invested in research into mitochondrial disorders and many exciting discoveries are being published that we hope will lead to treatments to slow the progression of these diseases for future cases.

24. How far away are we from a cure?

Our understanding of mitochondrial biology has improved along with drug design, and a number of compounds are on the horizon.

We are also in a better position to assess the efficacy of potential cures and drugs as a result of developing patient cohorts and because of highly organised and structured clinical trials.

There is hope.

25. How is Mitochondrial Disease Inherited?

The inheritance of Mitochondrial Disease is complicated.

Depending on the underlying genetic error, it can be passed down from the mother or father or both. It is also possible that the mistake may have arisen for the first time in the affected person.

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26. What is my risk for future children?

It is important to determine which type of Mitochondrial Disease inheritance is present (see Q25) in order to predict the risk of recurrence for future children.

If a family has a genetic diagnosis there are options to test future pregnancies (See Q27).

For families without a genetic diagnosis, making the decision to have another child involves a degree of risk. The level of risk involved can be estimated from the pattern of inheritance of the disease in the family.

27. Can I test a pregnancy to see if my unborn child will be affected

If you have a genetic diagnosis for your Mitochondrial Disease, it is possible to test a pregnancy using CVS or amniocentesis to see if the baby might be affected.

There is also the option of using an IVF procedure called Pre-Implantation Genetic Diagnosis (PDG) which can test embryos to see if they are affected.

Read more

28. What are my reproductive choices?

If you have already had an affected child then you are potentially at risk of this happening again (see Q26).  

There are a number of reproductive choices available to families facing these challenges and they include adoption, egg or sperm donation, IVF with Pre-implantation Genetic Diagnosis (PGD) and more recently Mitochondrial Donation Techniques.

Egg Donation

This involves using the egg of a donor woman combined with sperm of the father.  

This treatment is effective for both Mitochondrial DNA defects and for Nuclear DNA defects and ensures the resulting child will be free from Mitochondrial Disease.

The child will be genetically related to the father but not the mother.

Sperm Donation

This involves using the sperm of a donor male combined with egg of the mother.  

This treatment is only effective for Nuclear DNA defects but ensures the resulting child will be free from Mitochondrial Disease.

The child will be genetically related to the mother but not the father.

IVF with PGD (see Q28)

This technique involves IVF treatment using the mothers egg and the fathers sperm so the resulting child will be genetically related to both parents. The process involves creating a number of embryos through the normal IVF process and then screening these using a process called Preimplantation Genetic Diagnosis (PGD) to identify embryos that look healthy and are either free from disease or carry low levels of mutation.

The screening process is very effective for nuclear DNA mutations as it can give a definite yes or no answer.

Results from mitochondrial DNA mutations however may be less clear. Clinicians are usually able to advise families the % of faulty mitochondrial DNA which is then compared against theoretical disease thresholds. Borderline results however mean that families may not be able to get the assurance they need to take forward into pregnancy. Q28 gives more information on this area.

For some women who carry 'homoplasmic mutations' this technique will not be successful and for these families, and for families where PGD has not been successful, there has recently been a medical breakthrough called Mitochondrial Donation.

Mitochondria Donation

This technique involves using the mothers egg, the fathers sperm and the healthy mitochondria from a donor woman. The resulting child will be genetically related to both parents and will have a tiny 0.02% of mitochondrial DNA from the donor woman.

This treatment is only affective for mothers that carry Mitochondrial DNA defects but it can help some families that IVF with PGD cannot.

UK legislation was passed in Feb 2015 to allow this technique to be offered on a case by case basis to suitable affected families.

I want to know more about Mitochondrial Donation 

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29. Can we prevent Mitochondrial Disease?

Yes. Reproductive techniques like egg/sperm donation and PGD are currently able to prevent the transmission of nuclear mitochondrial DNA disease to the child, and also prevent the child passing on the disease to its future generations.

For families with mitochondrial DNA disease, until recently, only egg donation could achieve the same results.

In 2015 a new technique was introduced in the UK called Mitochondrial Donation. This is an IVF technique which uses the mother and fathers nuclear DNA combined with healthy mitochondria from a donor woman. This technique will prevent transmission of maternally inherited Mitochondrial Disease from mother to child and also ensure that child will not carry the disease to its future generations. 

Find out more

30. Are there links with other diseases?

For a long time, Mitochondrial Disease was considered a rare childhood disorder, however in the last decade it has been discovered that many more common disorders may have an underlying mitochondrial basis including Parkinson’s disease and Alzheimer’s disease.

In addition some forms of Cancer: Diabetes Mellitus, and Epilepsy can result from problems with mitochondrial function.

31. Is there any research that I can be involved in?

There are a number of different types of research study that families can get involved with, but whether you take part very much depends on what you want to get out of it.

Some studies involve using existing clinical data from routine follow ups and others require patient participation.

Some trials annonymise data (so you will not get direct personal feedback) and others will provide feedback to participants - either way, your involvement will add huge value to the understanding of this area of medicine. Some studies may not use medical data at all but instead may examine the social impact of this condition.

What exactly will be required from you and what will be reported back, will depend on the exact nature of the study you sign up to, so it is important to talk to your trial coordinator or clinician and understand what is involved.

We have more information on the kind of projects you can get involved with.

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32. Types of Mitochondrial Disease

Mitochondrial Disease is actually a term used to describe a group of diseases affecting energy production.

Further information on the following can be found by clicking here.

Alpers, Mitochondrial DNA Depletion Syndrome, Leigh Syndrome, Leber's Hereditary Optic Neuropathy (LHON), MELAS, MERRF, MNGIE, Mitochondrial DNA Deletions, NARP, Large Scale Mitochondrial DNA Deletions.