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Mitochondrial Disorders

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1 Mitochondrial Disorders on Sun Feb 21, 2010 6:50 am


Mitochondria are components of cells that are involved in metabolism and enzyme production. They are the energy factories of our cells. They also contain genetic material. Particular abnormalities in the mitochondrial genes are often associated with epileptic disorders. The metabolic disorders involving the mitochondria affect different parts of the body, including muscle and brain.

Mitochondria are inherited through the mother. Two mitochondrial disorders are often associated with epileptic seizures:

One is MELAS: Mitochondrial-myopathy, Encephalopathy, Lactic Acidosis (meaning too much lactic acid in the blood), and strokelike episodes. MELAS can lead to strokelike episodes at a young age (usually before 40), seizures, dementia, headaches, vomiting, unsteadiness, and ill effects from exercise. Persons with MELAS can have both generalized seizures (including myoclonic and tonic-clonic) and partial seizures.

The other mitochondrial disorder with epileptic seizures is MERRF: Myoclonic Epilepsy with Ragged Red muscle Fibers). MERRF is one of the Progressive Myoclonic Epilepsies. It can also be associated with hearing loss, unsteadiness, dementia, and ill effects from exercise. In addition to myoclonic seizures, patients with MERRF often have generalized tonic-clonic seizures that can be controlled with standard medications.

There are other mitochondrial disorders that do not fit clearly into the MELAS or MERRF syndromes but which can cause epilepsy and additional neurologic problems.

In the simplest terms, mitochondrial disease or cytopathy can ultimately be thought of as a deficiency of energy production. The other cell-specific functions that mitochondria perform may also give rise to disease symptoms, however. The degree of mitochondrial dysfunction, the organs involved, and environmental conditions (for instance, whether the person has another chronic illness) will determine the severity of the disease.
One factor in the variety of characteristics of these diseases is their many different causes:

  • inherited mutations in mitochondrial DNA or nuclear DNA
  • spontaneous mutations in mitochondrial DNA or nuclear DNA
  • environmental toxins
  • medications used to treat other diseases

Another factor is that problems with mitochondrial function may affect only certain organs, for reasons that are not entirely clear. A partial explanation for the difference may be that some tissues or organs (such as skin) have low energy requirements for functioning, whereas others (such as nerve cells) have high energy requirements. Nerve cells thus would be more sensitive to changes in energy. Variability may also be due to the person's stage of development. A growing and developing organ needs more energy than one that is mature, so subtle defects in energy metabolism would have a greater impact on a developing organ. Other variability may be due to processes that we do not yet understand.

All mitochondria come from the mother’s egg. The egg destroys the mitochondria in the sperm. It would seem reasonable to assume that if the mother’s mitochondrial DNA has a particular disease-causing mutation, then all mitochondria would have the same mutation and the disease associated with this mutation would be relatively similar from patient to patient. This does NOT occur, however. It is very rare for all mitochondrial DNA copies to have a specific mutation in a particular patient. Usually some of the mitochondria carry the mutation and the others are normal. This is called heteroplasmy.

Each child will carry the mother’s mitochondrial DNA mutation, although in different amounts. Varying percentages of mutated and normal mitochondria can change the severity and characteristics of a particular disease.

The interplay among the many genes and cells that must cooperate for cells to function is complex. Changes in this interaction can influence changes in the metabolic state produced by a particular mutation. These processes produce a spectrum of disease presentations, and can give rise to one hallmark of mitochondrial disease—identical mitochondrial DNA mutations may not produce identical diseases. This is called phenocopy.

On the other hand, different mutations may produce disorders that appear the same. This is called genocopy. In fact, mutations in nuclear DNA can give rise to syndromes that have the clinical features of a particular mitochondrial DNA mutation. For instance, patients with the disease syndrome called MELAS (mitochondrial myopathy, progressive encephalopathy, lactic acidosis, and stroke-like episodes) usually have a particular mitochondrial DNA mutation, but some have dysfunction of the mitochondria's energy-producing mechanism (electron transport chain complexes) instead.

The wide array of signs and symptoms of mitochondrial disease can make the physician’s head spin. No single symptom, sign, or test result points directly to a mitochondrial cytopathy. A patient can have a perfectly normal muscle biopsy and still have a disease-causing mitochondrial DNA mutation causing symptoms. Some doctors follow this rule: “When a common disease has features that set it apart from the pack, or when it involves three or more organ systems, think mitochondria."

If no single test defines a mitochondrial cytopathy, how can it be detected or defined? Many tests are evaluated together with the patient’s symptoms. Blood tests are performed to check serum levels of lactate, pyruvate, amino acids, and coenzyme Q10, and the acyl carnitine profile. Organic acids in the urine are evaluated. Magnetic resonance imaging (MRI) of the brain is also performed. Many centers now perform a new variation of the MRI, magnetic resonance spectroscopy (MRS). MRS gives the physician a real-time biochemical analysis of various areas of the brain. It can suggest a defect in oxidative phosphorylation within the brain, by the presence of lactate peaks.

If the results of the previous tests suggest a mitochondrial disease, then a muscle biopsy is performed. The most common site of muscle biopsy is the thigh muscle, vastus lateralis. Other muscles, including the heart, can be tested (as well as samples from the skin, liver, and blood), but fewer results are available for comparison to identify abnormalities.

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