Mitochondrial disorders, also called mitochondrial cytopathies, are a diverse group of diseases caused by damage to small structures found in human cells that are essential in converting food to energy. The result is decreased energy production and associated symptoms.
Cells are the building blocks of the human body, microscopic structures that are bound by a membrane and contain numerous components called organelles that are responsible for functions such as cell reproduction, transportation of materials, and protein synthesis. Cellular respiration, a process by which food molecules are converted into high-energy molecules used as a source of energy, takes place in structures called mitochondria. The energy produced by mitochondria is essential for cell functions.
Before the mid-twentieth century, little was known about mitochondrial disorders. The first diagnosis of a mitochondrial disorder occurred in 1959, and the genetic material of microchondria, called mtDNA, was discovered in 1963. In the 1970s and 1980s, as more was learned about the mitochondria and more mitochondrial disorders were discovered, the term "mitochondrial myopathies" (myopathy meaning a disease of muscle tissue) was coined to describe the group of diseases. Further research in the 1990s led to classification of mitochondrial disorders. As it became evident that tissues other than muscle could be affected by mitochondrial defects, the term "mitochondrial cytopathies" (cytopathy meaning cell disorder) was adopted.
Disorders in which skeletal muscle is the primary target of the mitochondrial dysfunction are called mitochondrial myopathies . Mitochondrial encephalomyopathies are disorders in which muscle and brain tissue is involved.
Common mitochondrial disorders
As of 2004 there were more than 40 distinct mitochondrial cytopathies. Some of the more common disorders include:
- Kearns-Sayre syndrome (KSS). Onset of KSS usually occurs before the age of 20. Symptoms include progressively constrained eye movements, droopy eye lids, muscle weakness, short stature, hearing loss, loss of coordination, heart problems, cognitive delays, and diabetes.
- Myoclonus epilepsy with ragged-red fibers (MERRF). MERFF is a mitochondrial encephalomyopathy in which a mitochondrial defect as well as a tissue abnormality called "ragged-red fibers" (an accumulation of diseased mitochondria) is found microscopically. The resulting symptoms include seizures, loss of coordination, short stature, build-up of lactic acid in the blood, difficulty speaking, dementia, and muscle weakness.
- Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). MELAS is a progressive mitochondrial disease that involves multiple organ systems including the central nervous system, cardiac muscle, skeletal muscle, and gastrointestinal system. Symptoms include muscle weakness, stroke-like events, eye muscle paralysis, and cognitive impairment.
- Leber hereditary optic neuropathy (LHON). LHON causes progressive loss of vision resulting in various degrees of blindness and primarily affects men over the age of 20. Heart abnormalities may also occur.
- Leigh syndrome. This degenerative brain disorder is usually diagnosed at a young age (e.g. before age two). Deterioration is often rapid with symptoms such as seizures, dementia, feeding and speech difficulties, respiratory dysfunction, heart problems, and muscle weakness. Prognosis is poor with death typically occurring within a few years of diagnosis.
- Myoneurogenic gastrointestinal encephalopathy (MNGIE). Key features include symptoms that mimic gastrointestinal obstruction and nervous system abnormalities. Other symptoms may include eye muscle paralysis, muscle weakness, loss of coordination, and brain abnormalities.
- Pearson syndrome. With symptoms usually first appearing in childhood, the characteristics of this rare syndrome include pancreatic dysfunction and anemia (low red blood cells). Difficulty gaining weight, diarrhea , and enlarged liver are other signs of Pearson syndrome.
- Neuropathy, ataxia, and retinitis pigmentosa (NARP). The symptoms implied by this disorder's name include nervous system abnormalities, loss of coordination, and progressive loss of vision. Developmental delays, dementia, and muscle weakness may also result. Onset usually occurs in childhood.
Approximately 1,000 to 4,000 children are born with mitochondrial disease in the United States each year. Typically, by the age of ten, approximately one in 4,000 American children is diagnosed with mitochondrial disease.
Causes and symptoms
Although mitochondrial disorders may be caused by distinctly different damage to the mitochondrial genetic material, and thus affect any of the hundreds of chemical reactions required to convert food and oxygen into energy, they all share a common feature: the ability of mitochondria to generate energy is damaged. Byproducts of the numerous reactions can begin to accumulate in the cells and interfere with other chemical reactions and over time damage the mitochondria further.
Inheritance of mitochondrial disorders
In many cases, a mitochondrial disorder is passed genetically from parent to child (inheritance). It can often be helpful for the type of inheritance to be determined, as parents can then make an educated decision about the risks of passing the condition on to another child or the risks of another family member developing the disease. Genetic defects may be passed through nuclear DNA (nDNA), the genetic material found in each cell that determines the majority of hereditary characteristics, or through mtDNA. Some types of mitochondrial disorder inheritance include:
- Autosomal recessive inheritance. Each individual has two sets of genes, one inherited from each parent. In some genetic diseases, a person needs to have two copies of a defective gene in order to show symptoms of the disease; if only one of the two genes is defective, the person is considered a carrier. In autosomal recessive inheritance, the affected individual has inherited a defective gene from each parent.
- Maternal inheritance. mtDNA is only passed from mother to child because the mitochondria of a sperm is located in the sperm's tail, which is not involved in conception. Some mitochondrial disorders are, therefore, only passed from mother to child.
- X-linked recessive inheritance. The sex of a child is determined through the inheritance of strands of DNA called chromosomes. A female child inherits two X chromosomes, while a male child inherits an X chromosome from one parent and a Y chromosome from the other. If a defective gene encoding for a disease is found on the X chromosome, then a male child cannot have a healthy copy of the gene (since he only has one X chromosome); therefore, he will develop the disorder. Female children are at less risk because they have to have two copies of the defective gene (one on each X chromosome) in order to develop the disease.
- Autosomal dominant inheritance. As opposed to autosomal recessive inheritance, only one defective copy of a gene needs to be inherited in order for an individual to develop the disease. Each successive child, therefore, has a 50 percent chance of developing the disorder.
In some cases, no other family members are affected by the disease and there appears to be no genetic link. These cases are called random or sporadic occurrences and may be caused by a number of environmental factors including certain drugs (e.g. medications used to treat human immunodeficiency virus [HIV] have been linked to mitochondrial damage), anorexia nervosa (a disease characterized by self-starvation), exposure to certain toxins, prolonged periods of insufficient oxygen, or older parental age (mtDNA mutations may accumulate over time).
Because more than 90 percent of the energy needed by the human body to function is generated by mitochondria, the effects of mitochondrial disorders can be farreaching. Research has shown that cells of the brain, nerves, skeletal muscles, liver, heart, kidneys, ears, eyes, and pancreas seem to be particularly affected because of their high energy requirements. Some of the more common symptoms of mitochondrial diseases by organ system include the following:
- brain: confusion, memory loss, headaches, seizures, developmental delays, and stroke-like episodes
- nerves: pain caused by nerve abnormalities (neuropathic pain), gastrointestinal problems linked to nerve abnormalities, abnormal sweating, and fainting
- skeletal muscles: muscle weakness, muscle cramping, muscle pain, loss of coordination, exercise intolerance, and poor growth
- liver: liver failure not due to excessive alcohol use and low blood sugar (hypoglycemia)
- heart: heart muscle weakness and disturbed electrical signals in the heart (called heart block)
- kidneys: abnormalities that cause difficulty with absorbing nutrients and electrolytes back into the body (called Fanconi syndrome)
- ears: hearing loss
- eyes: eye muscle paralysis, progressive loss of vision
- pancreas: diabetes (a group of conditions characterized by excessive urine excretion and persistent thirst) and pancreatic failure
Other symptoms include failure to thrive in infants, poor growth, short stature, fatigue, respiratory disorders, swallowing difficulties, and increased risk of infection.
When to call the doctor
The array of symptoms that are displayed by children suffering from mitochondrial disorders are common to many other diseases, and the age of onset can range from early infancy to adulthood. Often, the hallmark sign of a mitochondrial disorder that distinguishes it from other diseases with similar symptoms is additional features (such as the above symptoms) that do not normally appear with the non-mitochondrial disease. Parents should notify their healthcare provider if their child develops symptoms atypical for their previously diagnosed condition or if those symptoms get worse or recur with infection.
Because of the complex nature of mitochondrial disorders, physicians take a multi-faceted approach to diagnosing such diseases. The process usually starts with a comprehensive physical exam and evaluation of the patient's medical and family history. Often a neurological exam is performed to determine if there are any brain abnormalities. To diagnose a mitochondrial disorder and rule out other diseases, more extensive tests may need to be performed. Some examples are as follows:
- Initial evaluation. The first line of testing usually involves the least invasive methods, such as sending a sample of blood for evaluation. In some cases a diagnosis can be made based on blood tests; in others, blood tests may indicate that further testing is necessary.
- Secondary evaluation. These tests may be more intensive, more invasive, and/or carry more risks. Examples include lumbar puncture (spinal tap), urine collection, magnetic resonance imaging (MRI), additional blood tests, or electrocardiogram (ECG).
- Tertiary evaluation. Complex and/or invasive procedures such as skin or muscle biopsy (taking a small sample of tissue for microscopic evaluation) are considered tertiary tests. In some cases such tests are necessary to make a definitive diagnosis.
In some cases, a physician may not be able to diagnose the patient with a specific mitochondrial disorder even after extensive evaluation. Parents should, therefore, be advised that despite the complexity of testing for mitochondrial disorders, diagnosis is not always possible.
As of 2004, there are no cures for mitochondrial disorders. Treatment plans focus on delaying progression of the disease or reducing a patient's symptoms. The method of treatment depends on many factors, including the patient's disease, age, affected organs, and health status. Not all patients benefit from treatment; those with less severe disease generally respond better. Treatment may consist of vitamins , supplements, physical or occupational therapy, or traditional medications. Examples of these include:
- vitamins, such as B vitamins (thiamine, riboflavin, niacin, folate, biotin, and pantothenic acid), vitamin E, and vitamin C
- coenzyme Q10 (CoQ10), which is involved in cellular respiration in normal mitochondria
- levocarnitine (Carnitor), taken orally or intravenously, to replace a cofactor necessary in cellular respiration
- antioxidant therapy, a treatment under investigation that may help to keep mitochondrial damage under control
- physical or occupational therapy for myopathies
For some patients, avoiding physiological stressors such as extreme cold, extreme heat, poor nutrition , fasting, and lack of sleep may improve their condition. Alcohol, cigarette smoke, and monosodium glutamate (MSG, added to many Asian foods) may also exacerbate a mitochondrial disorder.
In some cases, a properly devised diet is necessary to avoid worsening symptoms. Parents of a child affected with a mitochondrial disorder may be referred to a dietician to help formulate a diet specific to his or her disease. The plan is individualized to the child and may include suggestions such as avoiding long periods of time without eating, eating small but frequent meals, increasing or decreasing the amount of fat consumed, and avoiding or supplementing with certain vitamins or minerals .
The prognosis of mitochondrial disease depends on many factors, including the specific disorder, the mode of inheritance, the age of onset, and what organs are affected. Two children suffering from the same mitochondrial disorder may have two distinctly different courses. In some cases, patients may be able to control their symptoms to a great degree with various treatments, or progression of the disease is slow. In other cases, the disease progresses rapidly and inevitably leads to death.
Prevention of inherited mitochondrial disorders is not possible unless parents decide against having more children. In the case of mitochondrial cytopathies that are caused by environmental factors such as certain drugs or toxins, avoidance of these substances may minimize the risk of developing mitochondrial disease.
Because of the potential of passing on inherited mitochondrial disorders to other children, parents may be interested in genetic counseling. Genetic counselors are health professionals who are trained to help families determine the risk or probability of developing or passing on a genetic disorder. Genetic testing, however, cannot determine with certainty if or when a child will develop a mitochondrial disease or what the severity will be.
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Schapira, Anthony, H. V., et al. Mitochondrial Disorders in Neurology. Kent, UK: Elsevier Science & Technology Books, 2002.
Cohen, Bruce H. and Deborah R. Gold. "Mitochondrial Cytopathy in Adults: What We Know So Far." Cleveland Clinic Journal of Medicine 68, no. 7 (July 2001): 625–42.
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Stephanie Dionne Sherk
Cellular respiration —The process by which food molecules are converted into high-energy molecules used as a source of energy.
Electrocardiagram (ECG, EKG) —A record of the electrical activity of the heart, with each wave being labeled as P, Q, R, S, and T waves. It is often used in the diagnosis of cases of abnormal cardiac rhythm and myocardial damage.
Mitochondrial inheritance —Inheritance associated with the mitochondrial genome which is inherited exclusively from the mother.
Ragged-red fibers —A microscopic accumulation of diseased mitochondria.