WHAT ARE MITOCHONDRIAL DISEASES?
Just as some diseases are named for the part of the body they affect (like heart disease), mitochondrial diseases are so-named because they affect a specific part of the cells of which our bodies are made. Specifically, mitochondrial diseases affect the mitochondria — tiny energy factories found inside almost all our cells.
1. Nervous system Seizures, spasms, developmental delays, deafness, dementia, stroke before age 40, visual system defects, poor balance, problems with peripheral nerves
2. Eyes Drooping eyelids (ptosis), inability to move eyes from side to side (external ophthalmoplegia), blindness (retinitis pigmentosa, optic atrophy), cataracts
3. Heart Cardiomyopathy (cardiac muscle weakness), conduction block
4. Liver Liver failure (uncommon except in babies with mtDNA depletion syndrome)
5. Kidneys Fanconi's syndrome (loss of essential metabolites in urine), myoglobinuria
6. Skeletal muscle Muscle weakness, exercise intolerance, cramps
7. Digestive tract Acid reflux, vomiting, chronic diarrhea, intestinal obstruction
8. Pancreas Diabetes
Mitochondria are responsible for producing most 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.
Nearly all our cells rely on mitochondria for a steady energy supply, so a mitochondrial disease can be a multisystem disorder affecting more than one type of cell, tissue or organ. The exact symptoms aren't the same for everyone, because a person with mitochondrial disease can have a unique mixture of healthy and defective mitochondria, with a unique distribution in the body.
Because muscle cells and nerve cells have especially high energy needs, muscular and neurological problems — such as muscle weakness, exercise intolerance, hearing loss, trouble with balance and coordination, seizures and learning deficits — are common features of mitochondrial disease. Other frequent complications include cataracts, heart defects, diabetes and stunted growth. Usually, a person with a mitochondrial disease has two or more of these conditions, some of which occur together so regularly that they're grouped into syndromes.
A mitochondrial disease that causes prominent muscular problems is called a mitochondrial myopathy (myo means muscle, and pathos means disease), while a mitochondrial disease that causes both prominent muscular and neurological problems is called a mitochondrial encephalomyopathy (encephalo refers to the brain).
Despite their many potential effects, mitochondrial diseases sometimes cause little disability. Sometimes, a person has enough healthy mitochondria to compensate for the defective ones. Also, because some symptoms of mitochondrial disease (such as diabetes or heart arrhythmia) are common in the general population, there are effective treatments for those symptoms (such as insulin or anti-arrhythmic drugs).
This booklet describes general causes, consequences and management of mitochondrial diseases, with an emphasis on myopathies and encephalomyopathies and a close look at the most common syndromes. These include:
· Kearns-Sayre syndrome (KSS)
· Leigh's syndrome
· mitochondrial DNA depletion syndrome (MDS)
· mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS)
· myoclonus epilepsy with ragged red fibers (MERRF)
· mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
· neuropathy, ataxia and retinitis pigmentosa (NARP)
· Pearson syndrome
· progressive external ophthalmoplegia (PEO)
WHAT CAUSES MITOCHONDRIAL DISEASES?
First, mitochondrial diseases aren't contagious, and they aren't caused by anything a person does. They're caused by mutations, or changes, in genes — the cells' blueprints for making proteins.
Genes are responsible for building our bodies, and are passed from parents to children, along with any mutations or defects they have. That means that mitochondrial diseases are inheritable, although they often affect members of the same family in different ways. (For more information about genetic mutations and mitochondrial disease, see "Does It Run in the Family?".)
The genes involved in mitochondrial disease normally make proteins that work inside the mitochondria. Within each mitochondrion (singular of mitochondria), these proteins make up part of an assembly line that uses fuel molecules derived from food to manufacture the energy molecule ATP. This highly efficient manufacturing process requires oxygen; outside the mitochondrion, there are less efficient ways of producing ATP without oxygen.
Proteins at the beginning of the mitochondrial assembly line act like cargo handlers, importing the fuel molecules — sugars and fats — into the mitochondrion. Next, other proteins break down the sugars and fats, extracting energy in the form of charged particles called electrons.
Proteins toward the end of the line — organized into five groups called complexes I, II, III, IV and V — harness the energy from those electrons to make ATP. Complexes I through IV shuttle the electrons down the line and are therefore called the electron transport chain, and complex V actually churns out ATP, so it's also called ATP synthase.
A deficiency in one or more of these complexes is the typical cause of a mitochondrial disease. (In fact, mitochondrial diseases are sometimes named for a specific deficiency, such as complex I deficiency.)
When a cell is filled with defective mitochondria, it not only becomes deprived of ATP — it can accumulate a backlog of unused fuel molecules and oxygen, with potentially disastrous effects.
Excess fuel molecules are used to make ATP by inefficient means, which can generate potentially harmful byproducts such as lactic acid. (This also occurs when a cell has an inadequate oxygen supply, which can happen to muscle cells during strenuous exercise.) The buildup of lactic acid in the blood — called lactic acidosis — is associated with muscle fatigue, and might actually damage muscle and nerve tissue.
Meanwhile, unused oxygen in the cell can be converted into destructive compounds called reactive oxygen species. (These are the targets of so-called antioxidant drugs and vitamins.)
ATP derived from mitochondria provides the main source of power for muscle cell contraction and nerve cell firing. So, muscle cells and nerve cells are especially sensitive to mitochondrial defects. The combined effects of energy deprivation and toxin accumulation in these cells probably give rise to the main symptoms of mitochondrial myopathies and encephalomyopathies.
WHAT HAPPENS TO SOMEONE WITH A MITOCHONDRIAL DISEASE?
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.
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.
A mitochondrial encephalomyopathy typically includes some of the above-mentioned symptoms of myopathy plus one or more neurological symptoms. Again, these symptoms show a great deal of individual variability in both type and severity.
Hearing impairment, migrainelike headaches and seizures are among the most common symptoms of mitochondrial encephalomyopathy. In at least one syndrome, headaches and seizures are accompanied by stroke (interruption of the brain's blood supply).
Fortunately, there are good treatments for some of these conditions. Hearing impairment can be managed using hearing aids and alternate forms of communication. Often, headaches can be alleviated with medications and seizures can be prevented with drugs used for epilepsy (anti-epileptics). Several drugs are currently under investigation for treating stroke.
Occupational therapy is important for children with mitochondrial myopathy.
In addition to affecting the musculature of the eye, a mitochondrial encephalomyopathy can affect the eye itself and parts of the brain involved in vision. (For instance, cataracts — thickening of the lenses that focus light in the eye — are a common symptom of mitochondrial encephalomyopathy.) Compared to muscle problems, these effects are more likely to cause serious visual impairment.
Often, mitochondrial encephalomyopathy causes ataxia, or trouble with balance and coordination. People with ataxia are usually prone to dizzy spells and falls, but can partly avoid those problems through physical and occupational therapy, and the use of supportive aids such as railings, a walker or — in severe cases — a wheelchair.
SPECIAL ISSUES IN MITOCHONDRIAL MYOPATHIES AND ENCEPHALOMYOPATHIES
Mitochondrial myopathy can lead to respiratory problems that require support from a ventilator.
Sometimes, these diseases can cause significant weakness in the muscles that support breathing.
Also, mitochondrial encephalomyopathies sometimes cause brain abnormalities that alter the brain's control over breathing.
A person with mild respiratory problems might require occasional supplemental oxygen, while someone with more severe problems might require permanent support from a ventilator. If you have a mitochondrial disorder, you should watch for signs of respiratory insufficiency (such as shortness of breath or morning headaches), and have your breathing checked regularly by a specialist.
Sometimes, mitochondrial diseases directly affect the heart. In these cases, the usual cause is an interruption in the rhythmic beating of the heart, called a conduction block. Though dangerous, this condition is treatable with a pacemaker, which stimulates normal beating of the heart. If you have a mitochondrial disorder, you may need to have regular examinations by a cardiologist.
Other Potential Health Issues
Some people with mitochondrial disease experience serious kidney problems, gastrointestinal problems and/or diabetes. Some of these problems are direct effects of mitochondrial defects in the kidneys, digestive system or pancreas (in diabetes), and others are indirect effects of mitochondrial defects in other tissues.
For example, rhabdomyolysis can lead to kidney problems by causing a protein called myoglobin to leak from ruptured muscle cells and build up in the bloodstream. This condition, called myoglobinuria, strains the kidneys' ability to filter waste from the blood into urine, and can cause kidney damage.
Special Issues in Children
Vision: Though PEO and ptosis typically cause mild visual impairment in adults, they're potentially more harmful in children with mitochondrial myopathies.
Because the development of the brain is sensitive to childhood experiences, PEO or ptosis during childhood can sometimes cause permanent damage to the brain's visual system. For this reason, it's important for children with signs of PEO or ptosis to have their vision checked by a specialist.
Developmental Delays: Due to muscle weakness, brain abnormalities or a combination of both, children with mitochondrial diseases may have difficulty developing certain skills. For example, they might take an unusually long time to reach motor milestones (such as sitting, crawling and walking). As they get older, they may be unable to get around as easily as other children their age, and they might have speech problems and/or learning disabilities. If your child is severely affected by these problems, he or she may benefit from physical therapy, speech therapy and possibly an individualized education program (IEP) at school.
Some children with mitochondrial myopathies experience developmental delays.
The brain's visual system can be affected in children with mitochondrial myopathy.
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). (See "Special Issues".)
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 SYNDROMES OCCUR WITH MITOCHONDRIAL DISEASE?
Note: Typically, these syndromes are inherited in either a maternal pattern () or a so-called Mendelian pattern (), and/or they're sporadic (), which means occurring with no family history. For more information about inheritance, see "Does It Run in the Family?"
Onset: before age 20
Features: This disorder is defined by PEO (usually as the initial symptom) and pigmentary retinopathy, a "salt-and-pepper" pigmentation in the retina that can affect vision, but often leaves it intact. Other common symptoms include conduction block (in the heart) and ataxia. Less typical symptoms are mental retardation or deterioration, delayed sexual maturation and short stature.
subacute necrotizing encephalomyopathy (MILS
= maternally inherited Leigh's syndrome)
Features: Leigh's syndrome causes brain abnormalities that can result in ataxia, seizures, impaired vision and hearing, developmental delays and altered control over breathing.
It also causes muscle weakness, with prominent effects on swallowing, speech and eye movements.
MDS: mitochondrial DNA
Features: This disorder typically causes muscle weakness and/or liver failure, and more rarely, brain abnormalities. "Floppiness," feeding difficulties, and developmental delays are common symptoms; PEO and seizures are less common.
encephalomyopathy, lactic acidosis and strokelike episodes
Onset: childhood to early adulthood
Features: MELAS causes recurrent strokes in the brain, which manifest as migrainelike headaches, vomiting and (less often) seizures, and can lead to permanent brain damage. Other common symptoms include PEO, general muscle weakness, exercise intolerance, hearing loss, diabetes and short stature.
epilepsy with ragged red fibers
Onset: late childhood to adolescence
Features: The most prominent symptoms are myoclonus (muscle spasms), seizures, ataxia and muscle weakness. The disease can also cause hearing impairment and short stature.
Onset: usually before age 20
Features: This disorder causes PEO, ptosis, limb weakness and gastrointestinal (digestive) problems, including chronic diarrhea and abdominal pain. Another common symptom is peripheral neuropathy (a malfunction of the nerves that can lead to sensory impairment and muscle weakness).
ataxia and retinitis pigmentosa
Onset: infancy to adulthood
Features: NARP causes neuropathy (see above), ataxia and retinitis pigmentosa (degeneration of the retina in the eye, with resulting loss of vision). It can also cause developmental delay, seizures and dementia.
Features: This syndrome causes severe anemia and malfunction of the pancreas. Children who survive the disease usually go on to develop KSS.
Onset: Usually in adolescence or early adulthood
Features: As noted above, PEO is often a symptom of mitochondrial disease, but sometimes it stands out as a distinct syndrome. Often, it's associated with exercise intolerance.
HOW ARE MITOCHONDRIAL DISEASES DIAGNOSED?
None of the hallmark symptoms of mitochondrial disease — muscle weakness, exercise intolerance, hearing impairment, ataxia, seizures, learning disabilities, cataracts, heart defects, diabetes and stunted growth — are unique to mitochondrial disease. However, a combination of three or more of these symptoms in one person strongly points to mitochondrial disease, especially when the symptoms involve more than one organ system.
To evaluate the extent of these symptoms, a physician usually begins by taking the patient's personal history, and then proceeds with physical and neurological exams.
DIAGNOSTIC TESTS IN MITOCHONDRIAL DISEASES
What It Shows
Clinical exam or oral history of family members
Can sometimes indicate inheritance pattern by noting "soft signs" in unaffected relatives. These include deafness, short stature, migraine headaches and PEO.
4. Electron microscopy
1. Detects abnormal proliferation of mitochondria and deficiencies in cytochrome C oxidase (COX, which is complex IV in the electron transport chain).
2. Detects presence or absence of specific proteins. Can rule out other diseases or confirm loss of electron transport chain proteins.
3. Measures activities of specific enzymes. A special test called polagraphy measures oxygen consumption in mitochondria.
4. May confirm abnormal appearance of mitochondria. Not used much today.
Lactate and pyruvate levels
2. Serum creatine kinase
1. If elevated, may indicate deficiency in electron transport chain; abnormal ratios of the two may help identify the part of the chain that is blocked.
2. May be slightly elevated in mitochondrial disease but usually only high in cases of mitochondrial DNA depletion.
2. Rare or unknown mutations
1. Uses blood sample or muscle sample to screen for known mutations, looking for common mutations first.
2. Can also look for rare or unknown mutations but may require samples from family members; this is more expensive and time-consuming.
The physical exam typically includes tests of strength and endurance, such as an exercise test, which can involve activities like repeatedly making a fist, or climbing up and down a small flight of stairs. The neurological exam can include tests of reflexes, vision, speech and basic cognitive (thinking) skills.
Depending on information found during the personal history and exams, the physician might proceed with more specialized tests that can detect abnormalities in muscles, brain and other organs.
The most important of these tests is the muscle biopsy, which involves removing a small sample of muscle tissue to examine. When treated with a dye that stains mitochondria red, muscles affected by mitochondrial disease often show ragged red fibers — muscle cells (fibers) that have accumulated mitochondria. Other stains can detect the absence of essential mitochondrial enzymes in the muscle. It's also possible to extract mitochondrial proteins from the muscle and measure their activity.
In addition to the muscle biopsy, noninvasive techniques can be used to examine muscle without taking a tissue sample. For instance, a technique called muscle phosphorus magnetic resonance spectroscopy (MRS) can measure levels of phosphocreatine and ATP (which are often depleted in muscles affected by mitochondrial disease). Also, a CT scan or magnetic resonance imaging (MRI) are tools for visualizing the overall structure of muscles.
CT scans and MRI can also be used to visually inspect the brain for signs of damage, and surface electrodes placed on the scalp can be used to produce a record of the brain's activity called an electroencephalogram (EEG).
A blood test might be ordered so the lab can look for a buildup of lactate or unused fuel molecules in the blood or cerebrospinal fluid (fluid that bathes the brain and spinal cord).
Similar techniques might be used to examine the functions of other organs and tissues in the body. For example, an electrocardiogram (EKG) can monitor the heart's activity, and a blood test can detect signs of kidney malfunction.
Finally, a genetic test can determine whether someone has a genetic mutation that causes mitochondrial disease. Ideally, the test is done using genetic material extracted from blood and from a muscle biopsy. It's important to realize that, although a positive test result can confirm diagnosis, a negative test result isn't necessarily meaningful.
DOES IT RUN IN THE FAMILY?
Often, a mitochondrial disease can be difficult to trace through a family tree. But since they're caused by defective genes, mitochondrial diseases do run in families.
To understand how mitochondrial diseases are passed on through families, it's important to know that there are two types of genes essential to mitochondria. The first type is housed within the nucleus — the part of our cells that contains most of our genetic material, or DNA. The second type resides exclusively within DNA contained inside the mitochondria themselves.
Mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can cause mitochondrial disease.
Most nDNA (along with any mutations it has) is inherited in a Mendelian pattern, loosely meaning that one copy of each gene comes from each parent. Also, most mitochondrial diseases caused by nDNA mutations (including Leigh's syndrome, MNGIE and even MDS) are autosomal recessive, meaning that it takes mutations in both copies of a gene to cause disease.
Unlike nDNA, mtDNA passes only from mother to child. That's because during conception, when the sperm fuses with the egg, the sperm's mitochondria — and its mtDNA — are destroyed. Thus, mitochondrial diseases caused by mtDNA mutations are unique because they're inherited in a maternal pattern (see illustration).
Another unique feature of mtDNA diseases arises from the fact that a typical human cell — including the egg cell — contains only one nucleus, but hundreds of mitochondria. The upshot is that a single cell can contain both mutant mitochondria and normal mitochondria, and the balance between the two will determine the cell's health.
This helps explain why the symptoms of mitochondrial disease can vary so much from person to person, even within the same family.
Imagine that a woman's egg cells (and other cells in her body) contain both normal and mutant mitochondria, and that some have just a few mutant mitochondria, while others have many. A child conceived from a "mostly healthy" egg cell probably won't develop disease, and a child conceived from a "mostly mutant" egg cell probably will.
Also, the woman may or may not have symptoms of mitochondrial disease herself.
The risk of passing on a mitochondrial disease to your children depends on many factors, including whether the disease is caused by mutations in nDNA or mtDNA.
A good way to find out more about these risks is to talk to a doctor or genetic counselor at your local MDA clinic. Also, see MDA's pamphlet, "Genetics and Neuromuscular Diseases."
MDA'S SEARCH FOR TREATMENTS AND CURES
With MDA's support, scientists continue to make significant progress in their quest to fully understand and treat mitochondrial diseases.
Because mitochondrial diseases can cause very diverse symptoms, they can be challenging to diagnose, and have historically been misdiagnosed as other diseases. MDA-funded scientists have helped improve diagnosis by carefully identifying the hallmark features of mitochondrial disease.
In an ongoing effort, MDA-funded scientists also have identified many of the genetic defects that cause mitochondrial diseases. They've used knowledge of those genetic defects to create animal models of mitochondrial disease, which can be used to investigate potential treatments. They've also designed genetic tests that allow accurate diagnosis of mitochondrial defects and provide valuable information for family planning.
Perhaps most important, knowing the genetic defects that cause mitochondrial disease opens up the possibility of one day repairing those defects via gene therapy.
While some of MDA's scientists pursue gene therapy for mitochondrial diseases, others are conducting clinical trials to evaluate the benefits of dietary supplements (such as creatine, carnitine and coQ10) and certain drugs (such as dichloroacetate, which can reduce lactic acidosis).
For people who have diseases caused by mtDNA mutations, MDA-funded scientists are working on several novel treatment strategies. For example, mtDNA isn't readily accessible to conventional gene therapy (because it's trapped inside mitochondria), so scientists are developing new gene therapy techniques to overcome that obstacle. Also, some scientists are investigating drug treatments and certain types of exercise to increase cellular levels of normal mtDNA relative to mutant mtDNA.
Children’s Mitochondrial Disease Network is the only parental and
professional based registered organization Within the
specializing in the complexities of Mitochondrial and sssociated disorders.
Mitochondria are small complex structures, which exist in every cell of the body (except red blood cells). The mitochondrion has been called the ‘powerhouse’ of the cell, as these tiny structures produce most of the energy, which we all need to grow and live. Those organs in the body, which require a lot of energy to work properly, are particularly dependent on well functioning mitochondria. The most energy dependent organs are the brain, heart, skeletal muscle, kidney, endocrine glands and bone marrow and these are the organ systems commonly affected in mitochondrial diseases.
There are from one to several hundred mitochondria in each cell and each mitochondrion contains the complex molecules necessary to carry our energy making chemical reactions. Mitochondria perform many functions necessary for cell metabolism but the energy producing pathways are the most important. These pathways allow us to break down carbohydrate, fat and oxygen to live. Electrons from these food molecules are passed down a series of complex molecules called the electron transport chain. The final molecule in the chain, cytochrome oxidase, passes the electrons to oxygen
One unique feature of mitochondria is that they have there own DNA molecules, mitochondrial DNA, which carries the genes containing the genetic message for several critical components of the electron transport chain.
What is a Mitochondrial Disease?
When enough mitochondria are not working correctly a disease may result. Mitochondrial diseases often involve the brain because of the tremendous energy requirements of the brain cells. Mitochondrial diseases are very variable in their features so called clinical heterogeneity.
The variability results from the fact that different organ systems contain different amounts of diseased mitochondria and only those tissues with a high percentage of diseased mitochondria will be functional impaired. Mitochondrial diseases are whole body diseases but the exact features of the disease vary from one patient to another. Some patients will have predominately brain disease or nerve disease. Others will have muscle disease (mitochondrial myopathy), cardiac disease (cardiomyopathies), endocrine, renal or bone marrow disease or a mixture of these and or other features.
Many mitochondrial diseases result in the accumulation of organic acids in the body. These are usually normal metabolic intermediates but when present in excess, the acidosis itself may be damaging or even life-threatening. Lactic acid accumulation is a common problem in mitochondrial diseases.
We used to think of mitochondrial diseases as rare childhood disorders. Recently it has been discovered that many commoner disorders such as diabetes and ischemic heart disease have, in some cases, a mitochondrial basis. Also, diseases of aging such as Parkinson’s disease and Alzheimer’s disease may result in part from mitochondrial failure (The role that mitochondrial abnormalities play in the cause of these diseases remains to be established). In fact, the aging process itself may be due to a lifetime of damage to mitochondria through oxidative stress and accumulated damage to mitochondrial proteins and mitochondrial DNA.
Genetics of Mitochondrial Diseases?
Some mitochondrial diseases are clearly inherited and those involving mitochondrial DNA may be inherited through the maternal side of the family as almost all mitochondria come from the mother. Most inherited mitochondrial diseases however are so called nuclear DNA defects with inheritance from either the mother or father, or in most cases both. This latter inheritance
How are Mitochondrial Diseases diagnosed?
Because of the multiple organ systems involved and the variation in the age of onset, mitochondrial diseases may be difficult to recognize. Even within the same family the same disease may affect individuals differently. A severe childhood disease such as Leigh’s syndrome may occur in the same family with later onset adult neurodegenerative disease. In some families mitochondrial myopathy has found some members with deafness and diabetes in others strokes along with a mixture of other symptoms. As well as the history and physical examination, blood and urine specialized tests together with brain CT or MRI scanning and skin and muscle biopsy are often needed to make a diagnosis. Patients should be referred as soon as possible to a specialist centre with expertise in metabolic and mitochondrial diseases.
What Treatments are available? (1)
In the New Millennium treatments for mitochondrial diseases are not very effective. Some effects of these diseases can be treated such as cardiac arrhythmia, seizure disorders, renal bicarbonate loss and hypoglycaemia.
When lactic acid accumulation seems to be a major problem an experimental drug Dichloroacete DCA, will lower the lactic acid. Although conclusive evidence of efficacy is not yet available, most doctors working with mitochondrial diseases treat their patients with cofactors and vitamins, which are thought to help impaired metabolic pathways. These treatments include combinations of Coenzyme Q10, L-Carnitine, Niacin, Thiamine, Biotin and Riboflavin. Special diets can be helpful.
Some patient’s benefit by high fat diets with restriction of simple carbohydrates. Fructose restriction may help.
Other patients need high carbohydrate intake with particular supplementation of complex carbohydrates such as uncooked cornstarch.
Only with a through medical evaluation, best carried out in a centre specializing in metabolic & mitochondrial diseases, can the optimal treatment regime for each patient be chosen.
What does the future hold? (1a)
There is no convincing evidence to date of any clear benefit of drug therapies in most archetypal mitochondrial disorders or those neurodegenerative conditions with evidence of mitochondrial dysfunction, and therefore attention has turned to the development of genetic therapies and the possibility of Neuro protection.
New horizons and hopes may lie with genetic strategies. Techniques for manipulating the mitochondrial genome are now being investigated. Whereas nuclear manipulation would necessitate treatment for life, manipulation of the mitochondrial genome would result in a one-off treatment thus providing a pattern is termed autosomal recessive and in this case the risk of reoccurrence in a sibling is 25% or one in 1 in 4. Most childhood onset mitochondrial diseases are inherited although in some cases the affected child seems to be the only affected family member.
Diseases resulting from mitochondrial deletions of large parts of the mitochondrial DNA molecule are usually sporadic without other affected family members. Genetic counseling is complex for mitochondrial diseases.
Pre-natal testing is only available for a few disorders.
“CURE” for Mitochondrial Disorders.
None Known at this time!