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WHAT IS MITOCHONDRIAL DISEASE?
The United Mitochondrial Disease Foundation offers this analogy to help you understand. If your power goes out in your home, your food spoils, your heating/air conditioning does not work, and you’re left in darkness. You call your local power supplier to report the problem.
The Mitochondria is the part of the cell responsible for energy production. It is very much like the power supplier that provides energy to your home. If the mitochondria is defective, your body cannot function as it should. The brain becomes impaired, muscles start to twitch spastically and weaken, the heart does not pump correctly, vision becomes impaired and the list can go on. For many children and adults with mitochondrial disease, this is exactly what they experience.
To give you a more “scientific explanation”, look at this picture of a mitochondrion, showing you the basic structure of a mitochondrion, which are present in every cell in our bodies: 
Mitochondria are the powerhouses of the human cell; they convert the energy stored in sugars and fats into adenosine triphosphate (ATP), the essential energy molecule of all animals.
This energy production is carried out on a complex folded inner membrane of the mitochondria (see the picture above). Every muscle cell is filled with mitochondria, combining sugars or fats with oxygen to yield water and ATP. Without this ATP, we would die, having no “power” left. Mitochondrial cytopathies have a diverse range of symptoms, and span many (all) organ systems.
There is such a large number of biochemical and genetic defects, that currently a predictable clinical course does not exist. Using the description above, the analogy of a power supplier not supplying enough energy is a good one. The mitochondrion in the above picture is only one of many in your cells.
The reason people manifest with SO many different problems is based on the percentage of “bad” mitochondria that get assigned to that part of the body. In our own family, some kids obviously have a higher percentage of bad mitochondria in their muscles than some of their siblings, while others have more brain (neurological) problems. This chart shows you a basic idea of how this can happen. Keep in mind that men do not contribute mitochondria, but that does not mean that only the mother causes mitochondrial disease, as there can be mutations.
Here’s the simplest way to explain what happens. The food we eat gets broken down and assigned in various fashion. The fats and sugars go through processing, and there’s quite a bit involved in this. If you get into this stuff more, you’ll hear all about the respiratory chain and ATP, which is the end result, or energy. The mitochondria in a cell have to go through five “complexes” to create energy. An error in any of those complexes is bad, but obviously there can be varying degrees of how big the error is, and where it occurs in the energy making process. Mitochondria are responsible for producing 95% of the energy that’s needed for our cells to function. In fact, they provide such an important source of energy that a typical human cell contains hundreds of them.
A mitochondrial disease can shut down some or all the mitochondria, cutting off this essential energy supply. Because muscle cells and nerve cells have especially high energy needs, muscular and neurological problems are common features of mitochondrial disease. MDA uses this picture to help illustrate:
When Should I Suspect Mitochondrial Disease?
As you read this, it may be nothing like what your child has. When should you investigate mitochondrial disease in your child, or even in yourself? Here are some “considerations” of when to think about mitochondria:
1. Consistently elevated lactate levels in the blood.
2. A “common disease” (i.e. autism, cerebral palsy, lots of others) has atypical features that set it apart from the pack.
3. Three or more organ systems are involved.
4. Recurrent setbacks or flares in a chronic disease occur with infections.
5. Above “rules of thumb” from Mitochondrial News, Spring 2000 Issue by Dr. Robert K. Navaiaux.
WHAT HAPPENS TO SOMEONE WITH A
MITOCHONDRIAL DISEASE?
Myopathy – The main symptoms of mitochondrial myopathy are muscle weakness and wasting, and exercise intolerance. It’s important to remember that the severity of any of these symptoms varies greatly from one person to the next, even in the same family.
Weakness and wasting usually are most prominent in muscles that control movements of the eyes and eyelids. Two common consequences are the gradual paralysis of eye movements, called progressive external ophthalmoplegia (PEO), and drooping of the upper eyelids, called ptosis. Often, people automatically compensate for PEO by moving their heads to look in different directions, and might not even notice any visual problems. Ptosis is potentially more frustrating because it can impair vision and also cause a listless expression, but it can be corrected by surgery, or by using glasses that have a “ptosis crutch” to lift the upper eyelids.
Jack experiences generalized muscle weakness and tires easily because of a suspected mitochondrial myopathy.
Mitochondrial myopathies can also cause weakness and wasting in other muscles of the face and neck, which can lead to slurred speech and difficulty with swallowing. In these instances, speech therapy or changing the diet to easier-to-swallow foods can be useful. Sometimes, people with mitochondrial myopathies experience loss of muscle strength in the arms or legs, and might need braces or a wheelchair to get around.
Exercise intolerance, also called exertional fatigue, refers to unusual feelings of exhaustion brought on by physical exertion. The degree of exercise intolerance varies greatly among individuals. Some people might only have trouble with athletic activities like jogging, while others might experience problems with everyday activities like walking to the mailbox, or lifting a milk carton.
Sometimes, exercise intolerance is associated with painful muscle cramps and/or injury-induced pain. The cramps are actually sharp contractions that may seem to temporarily lock the muscles, while the injury-induced pain is caused by a process of acute muscle breakdown called rhabdomyolysis. Cramps or rhabdomyolysis usually occur when someone with exercise intolerance “overdoes it,” and can happen during the overexertion or several hours afterward.
HOW ARE MITOCHONDRIAL DISEASES TREATED?
While mitochondrial myopathies and encephalomyopathies are relatively rare, some of their potential manifestations are common in the general population. Consequently, those complications (including heart problems, stroke, seizures, migraines, deafness and diabetes) have highly effective treatments (including medications, dietary modifications and lifestyle changes).
It’s fortunate that these treatable symptoms are often the most life-threatening complications of mitochondrial disease. With that in mind, people affected by mitochondrial diseases can do a great deal to take care of themselves by monitoring their health and scheduling regular medical exams.
Instead of focusing on specific complications of mitochondrial disease, some newer, less-proven treatments aim at fixing or bypassing the defective mitochondria. These treatments are dietary supplements based on three natural substances involved in ATP production in our cells.
One such substance, creatine, normally acts as a reserve for ATP by forming a compound called creatine phosphate. When a cell’s demand for ATP exceeds the amount its mitochondria can produce, creatine can release phosphate (the “P” in ATP) to rapidly enhance the ATP supply. In fact, creatine phosphate (also called phosphocreatine) typically provides the initial burst of ATP required for strenuous muscle activity.
Another substance, carnitine, generally improves the efficiency of ATP production by helping import certain fuel molecules into mitochondria, and cleaning up some of the toxic byproducts of ATP production. Carnitine is available as an over-the-counter supplement called L-carnitine.
Finally, coenzyme Q10, or coQ10, is a component of the electron transport chain, which uses oxygen to manufacture ATP. Some mitochondrial diseases are caused by coQ10 deficiency, and there’s good evidence that coQ10 supplementation is beneficial in these cases. Some doctors think that coQ10 supplementation might also alleviate other mitochondrial diseases.
Creatine, L-carnitine and coQ10 supplements are often combined into a “cocktail” for treating mitochondrial disease. Although there’s little scientific evidence that this treatment works, many people with mitochondrial disease have reported modest benefits. At the very least, there appear to be almost no harmful side effects to the three supplements when they’re taken in moderation, but you should consult your doctor or MDA clinic director before taking any of them.
WHAT ARE MITOCHONDRIA?
Mitochondria are like little “factories” in each of the cells of the body that are responsible for making 95% of the body’s source of energy. The cells in the body, and especially in organs such as the brain, heart, muscle, kidneys and liver, cannot function normally unless they are receiving a constant supply of energy. The energy is produced in the form of a chemical called ATP (adenosine triphosphate) that is used by the body to drive the various reactions essential for body functioning, growth and development. A number of biochemical reactions that occur in an ordered sequence within the mitochondria are responsible for this process of ATP production. These reactions are under the control of special proteins called enzymes. The genes found within the mitochondria contain the information that codes for the production of some of these important enzymes.
WHAT ARE THE BIOCHEMICAL REACTIONS THAT
OCCUR IN THE MITOCHONDRIA?
The biochemical processes which occur in the mitochondria and produce energy are known as the “mitochondrial respiratory chain”. This “chain” is made up of five components called Complex I, II, III, IV and V. Each of these complexes are made up of a number of proteins. The instructions for these proteins to be produced by the cells are contained in a number of different genes.
There are over 80 different genes needed to produce the components of the mitochondrial respiratory chain. Some of these genes are found in mitochondria rather than in the nucleus.
Changes (mutations) in any of these mitochondrial genes that make them faulty can result in biochemical problems due to absence or malfunctioning of the enzymes involved in the respiratory chain complexes. This leads to a reduction in the supply of ATP. This can have severe consequences, resulting in interference of body functions including any of the following, either in isolation or in various combinations.
EXAMPLES OF THE IMPACT OF FAULTY (MUTATED)
MITOCHONDRIAL GENES
General: small stature and poor appetite
Central nervous system: developmental delay / intellectual disability, progressive neurological deterioration (dementia such as the late-onset form of Alzheimer disease), seizures, stroke-like episodes (often reversible), difficulty swallowing, visual difficulties and deafness Skeletal and muscle: floppiness, weakness and exercise intolerance Heart: heart failure (cardiomyopathy) and cardiac rhythm conditions Kidney: problems in kidney function
CAN MUTATIONS IN THE MITOCHONDRIAL GENES BE INHERITED?
The number of mitochondria in every cell of a person’s body varies from a few to hundreds. All of these mitochondria, and therefore the DNA within the mitochondria, descend from the small number of mitochondria present in the original egg cell at the time of that person’s conception. The sperm does not contribute any mitochondria to the baby.
Thus an individual’s mitochondria are only inherited from his or her mother. A change in one of the mitochondrial genes that makes it faulty (mutation) can therefore be passed by the mother in her egg cells. As most of the mother’s egg cells carry the same mitochondrial mutation, the risk of this mother having another affected child with the mitochondrial condition is high. This pattern of inheritance is therefore referred to as maternal inheritance.
The egg cell contains many mitochondria, each having on average one to several copies of the mitochondrial genes. If a particular gene in every mitochondrion in an egg cell is faulty and therefore is sending the incorrect instructions, the disruption to energy production would be so severe that the early embryo would probably not survive. Thus the fact that a person survives to birth and is affected with a mitochondrial condition, means that they would have inherited two types of mitochondria from his or her mother: some containing the correct copy of the gene, and some containing the faulty gene.
The correct copy of the mitochondrial gene will still be able to send the correct instructions, but the amount of energy produced may be impacted and may result in a mitochondrial condition. On the other hand, having some mitochondria with a faulty gene may cause no problem at all as described in the video above.
AN EXAMPLE OF MITOCHONDRIAL (MATERNAL)
INHERITANCE
In some cases, the change in the mitochondrial gene occurs for the first time in the egg or at the time of fertilisation of the egg: a new or spontaneous mutation. In this case the affected person is the first in the family to be affected by the condition and the condition is described as sporadic.
Usually, however, the mitochondrial mutation is inherited from a mother whose own cells, including her egg cells, contain both correct and faulty copies of this mitochondrial gene. An example of a pattern of inheritance in a family of a genetic condition due to a faulty gene in the mitochondria.
The mother has one or more faulty mitochondrial genes but is not affected because she has enough correct copies to enable most of the mitochondria in her cells to work correctly. While she has passed on these faulty mitochondrial genes to her children through her egg, not all are affected by the condition.
This is because there is a “threshold effect” with mitochondrial faulty genes. Because of the way the mitochondria are randomly distributed into the egg cells when they are forming in the ovary, each egg cell’s individual mitochondrial composition may vary from mostly correct to mostly faulty. Therefore, all of the children of this mother, regardless of the sex of the child, would inherit some faulty mitochondria, but the child would only develop symptoms if the proportion of mitochondria with the faulty gene reached a critical level which interfered with energy production in the vulnerable body organ.
It is only when there are so many copies of the faulty mitochondrial genes present in the cells that the correct copies are unable to provide enough correct gene product, and the person will be affected by the condition. So even though two of her children who are unaffected have inherited the faulty mitochondrial genes, they have more correct copies than faulty copies.
The shaded individuals are all affected by the condition. Importantly, while not all of their mitochondrial genes are faulty, the number of mitochondria containing faulty genes is above the threshold for causing the condition.
While her son is affected, that son’s children are not at risk for inheriting the condition as the mitochondria are only passed to children from the mother through the eggs.
Her daughters are at risk of having an affected child, regardless of whether they themselves are affected. It is difficult to give a precise estimation of this risk as it will depend on how many faulty mitochondria are in the egg at the child’s conception.
CAN PRENATAL DIAGNOSIS BE USED FOR
MITOCHONDRIAL CONDITIONS?
While it is possible to test for the presence or absence of some faulty mitochondrial genes and their products during pregnancy, it is very likely that prenatal testing for a mitochondrial DNA mutation would give an incorrect or unhelpful result.
On the one hand, the prenatal test could predict that the baby would not be affected when in fact the baby could turn out to be affected. Alternatively, if the testing showed the baby did have the faulty mitochondrial gene, it is not possible at this stage to reliably predict how severely the baby would be affected.
Genetic counselling can provide the most current information on the availability and appropriateness of testing for mitochondrial conditions, either in an affected person or during pregnancy.
Mitochondrial Disease - Planting the Seeds To Save Our Son 