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POSITIVE EFFECTS OF HYPERBARIC OXYGENATION IN CERTAIN MITROCHONDRIAL CYTOPATHIES
“All life takes place on a cellular level. This is the first scientific proposal that hyperbaric oxygenation may selectively turn mitochondrial genes on and off.”
- Richard A. Neubauer, M. D.
INTRODUCTION
The simplest life on earth, as we know it, occurs in cells. Over the millennia, as cells evolved into more complex organisms, the new life depended upon the integrated and coordinated activities of thousands, millions and even billions of cells, each one requiring appropriate oxygen and glucose for respiration, metabolism, production of energy, adaptation, reproduction and overall survival.
For cells to carry out their unique functions they require a variety of foods with which to build their various cellular structures as well as their unique proteins, lipids and carbohydrates and from which the cells extract the energy to carry on all their vital activities.
The energy is derived in a series of biochemical reactions which involves the burning of sugar (glucose) in the foods animals eat with the oxygen they breathe. Normally when animals living on land, including humans, take a deep breath they inhale air containing 19-21% oxygen. From here on we will limit the discussion to humans, keeping in mind that similar activities, with variations in the details, also occur in other living organisms, especially mammals, the group of organisms to which humans belong.
The inhaled oxygen is not only dissolved in the bloodstream but it also binds to a molecule in the red blood cell called hemoglobin. The dissolved and bound oxygen is then transported through all of the blood vessels down to the tiniest capillaries. The bound oxygen is released, and along with the dissolved oxygen, diffuses to the individual cells of tissues and organs. Then the carbon dioxide, produced by the metabolism of the cells, is bound to the hemoglobin and transported to the lungs for elimination from the body.
THE AMAZING EXPERIMENT
Before discussing the transport of oxygen and its utilization by the cells, it is important to note that if the circulation is blocked such as it is in gangrene, myocardial infarction (heart attack) or in stroke, the consequences are deleterious. Even small reductions in blood flow will reduce the delivery of oxygen to the tissues and organs. Dr. Ite Boerema of Holland, in 1960, took a group of pigs from a farm and removed every drop of blood from them. He then substituted an artificial blood plasma to keep the circulation working and the heart pumping and put them into a hyperbaric chamber. Under hyperbaric oxygen conditions, even without a drop of blood, every organ functioned normally. Being frugal, he re-transfused half of the pigs and returned them to the farm. The other half were subjected to organ examination. Even with the total lack of blood there were no abnormalities in any organ: heart, lung, brain, kidneys, spleen, bone. This was an extremely important observation and showed clearly that life could be supported in a mammal without blood (red blood cells). This remarkable observation was very influential in the development of the field of hyperbaric medicine. It also introduced the use of hyperbaric oxygen as a substitute for blood transfusion to the Jehovah’s Witnesses.
Let us now return to the release of oxygen from the hemoglobin in the capillaries. Each step in the process of transporting oxygen to cells is important. The last step, the breaking off of the oxygen from the hemoglobin and its subsequent diffusion to the cells and their utilization of it is very important. It is at these last stages that the cells are going to use the oxygen to convert the energy from glucose into a chemical compound that drives the life processes. This last step is energy laden.
THE CELLS
Cells are the building blocks of all living organisms. Each cell has a center called the nucleus containing the genetic information for building and repairing and functioning of the cells. The rest of the cell, the material outside the nucleus to the edge of the cell (the cell membrane) is called the cytoplasm (the liquid-gel portion of the cell). The cytoplasm contains essential sub- cellular structures (organelles); one of the most important being the mitochondria, where energy is obtained in a form that can be utilized by the cell.
THE CHROMOSOMES
The nucleus of every human cell (except the mature red blood cells which have no nucleus) contains 46 chromosomes (23 pairs); one chromosome of each pair is derived from each parent. The only other exception to the 23 pair distribution is the reproductive cells. The male sperm and female egg each contain 23 chromosomes. During fertilization one of the chromosomes from the mother pairs up with its corresponding chromosome from the father to produce a cell containing 23 pairs of chromosomes. Twenty two pair are autosomal chromosomes and one pair are the sex chromosomes. Each chromosome contains genes which direct growth, development and function of the human body.
THE GENES
The genes, located on the chromosomes are the basic units of hereditary. One of the major functions of genes is to direct the synthesis of proteins. Thus, genes create proteins and proteins create us. Proteins are formed on the instructions found within the specific genes and consist primarily of amino acids. Proteins are the body’s work horse, carrying out chemical structural function within the cells and on higher levels of biological complexity, tissues and organs. Like DNA and RNA, (to be discussed below) proteins are three dimensional. A faulty gene can create a misshapen protein which, in turn, alters its function.
DNA & RNA
Genes are composed of a complex chemical called deoxyribonucleic acid (DNA). DNA is the chemical basis of genetics and heredity. DNA is in the form of a double helix molecule which encodes the unique genetic blueprint of cells’ individual traits. DNA is composed of four compounds called nucleotides. These nucleotides consist of two purine and two pyrimidine containing compounds. The purines are Adenine (A), and Guanine (G) and the pyrimidines are Thymine (T) and Cytosine (C). These four compounds fit together in a special way: The A always pairs with T. The G pairs with C. Any disarrangement of this complex puzzle may represent a misspelling of the message thereby sending wrong instructions to the cell leading to a mis-wired development or function.
Every human baby is 99.9% identical in DNA make up to every other human baby. It is the slightest deviation of only 0.1% that makes us unique individuals. In fact we are 98% identical in DNA to the great apes (chimpanzees). Even after billions of years of evolution we are 97% identical to the DNA in the yeast molecule. From comparative physiology and biochemistry we learn that what occurs in other organisms, especially on the molecular level of biologic
organization, may well occur in other living species as well. Thus, studies in yeast could profoundly influence our understanding of what happens in mammals, including humans.
RNA (ribonucleic acid) is an information encoded strand of nucleotides similar to DNA but with two slight changes; one of the pyrimidines, thymine, is replaced by a different one, uracil, and deoxyribose is replaced by a different five carbon sugar, ribose. DNA needs RNA in order to carry out it’s instructions. There are several types of RNA, each with a slightly different function. For example, mRNA (messenger RNA) mediates between DNA and proteins. tRNA (transfer RNA) works to line up the amino acids correctly. These amino acids are bound together to form proteins. The process of protein synthesis occurs in cellular organelles called ribosomes. Ribosomes are composed of protein and a third kind of RNA, rRNA (ribosomal RNA).
Genes are composed of segments of long DNA molecules which have their sequences transcribed onto messenger RNA, which then serves as a template for protein symthesis. Basically, DNA codes for the structure of messenger RNA, and mRNA codes for the structure of the specific proteins. Each gene is responsible for the structure of a specific protein.
In the 1990s another type of RNA, microRNA, was discovered. (The basic structure of DNA had not even discovered until 1953). MicroRNA is a very short and unusual piece of RNA. Instead of synthesizing proteins, this tiny molecule latches onto messenger RNA, causing its destruction. Without messenger RNA no protein is produced. In effect the gene for that particular protein has been silenced. Micro RNA was originally thought to be an oddity or anomaly in a single species but has now been identified in various plants and animals - 200 in humans alone.
Protein production is a highly regulated process. The process of turning a gene on or off, depending on the cell’s need for a particular protein, is called regulation of gene expression. Gene regulation is an essential part of life and is also critical for cellular response to metabolic needs. Since every cell in an organism contains the same genetic blueprint, different cell types are created by turning on and turning off different genes at different times during development. It is gene expression that allows stem cells to become unique cell types by being turned on (“expressed”) or off (“silenced”) in just the right combinations resulting in stem cells producing either heart cells, bone cells or brain cells, etc. The discovery of microRNA helps us to begin to understand these complex biological processes. It is now suspected that silencing particular genes at just the right times - a process called RNA interference - will push genetically identical cells down different paths of development, enabling some to perceive light while others digest food.
One of the important areas of research in modern biochemistry and developmental biology is learning about conditions and factors that turn genes on and off. In yeast it has been learned that oxygen is one of these factors.
THE MITOCHONDRIA & ENERGY SYNTHESIS
Oxygen is utilized in the cell primarily in the organelle called a mitochondrion (singular). Cells have many mitochondria (plural) depending on the specific function(s) of the cells and the amount of energy they require to carry out their functioning. Mitochondria are essential to every cell in the body. In 1963, it was discovered that mitochondria even contain their own genetic material (mtDNA) which is separate from the genetic material found in the cell nucleus (nDNA). Mitochondria are responsible for processing oxygen and converting the energy stored in the chemical structure of the foods we eat into a form that cells can use as a driving force for
all essential cell functions. Energy is produced in the form of a chemical compound called Adenosine triphosphate (ATP).
ATP is the universal currency of energy for all living organisms, i.e. all living organisms convert the energy in food to ATP. ATP is transported from the mitochondria to the cytoplasm (the liquid-gel portion of a cell) for its use in multiple cell functions.
MITOCHONDRIAL DISEASES
Mitochondrial diseases - now known as mitochondrial cytopathies - vary in clinical conditions depending upon the disturbance in the genetic make up of the mitochondria. Much information has been discovered since the 1940's and 50's when the first patient was diagnosed with a mitochondrial disease. Currently, there are over 40 known (identified) mitochondrial cytopathies . The main factor among these diseases is that the mitochondria are unable to completely burn the food with oxygen in order to generate sufficient energy (ATP) to sustain the integrated and coordinated functions of the cells and, thereby the functions of tissues and organs. These processes require numerous chemical reactions, all exquisitely coordinated, in order to have a continuous supply of energy to sustain life.
Incompletely burned food that accumulates may act as (a) poison(s) inside the body. These poisons can stop other chemical reactions that are essential for cell survival, making the energy crisis worse. In addition, some of these poisons can act as free radicals, highly reactive chemicals which readily form harmful compounds with other molecules. Free radicals can damage the mitochondrial DNA which has very limited repair abilities.
Mitochondrial diseases are classified according to the organ systems affected and the symptoms that are present. In certain cases only one organ is involved while in other patients multiple organs may be affected, and each system may have a wide variance of dysfunction. Depending upon how severe the mitochondrial disorder is, the illness may range in severity from mild to fatal. Mitochondrial cytopathies may affect any system of the body from the brain to the eyes, ears, gastrointestinal system, muscles, heart, liver, pancreas, thyroid, immune system, etc. or any combination of the above. This essentially creates an infinite number of manifestations of mitochondrial disease.
In the United States, by the age of 10, approximately 4,000 children will be diagnosed with or develop mitochondrial diseases. Between one thousand and four thousand children per year are born with some type of mitochondrial disease in the US.
Many diseases of aging have also been found to have defects in mitochondrial function in adults; including, but not limited to Type II diabetes, Parkinson’s disease, artherosclerosis, heart disease, stroke, Alzheimer’s and cancer. It must be noted that many medications and toxins may injure mitochondrial function at any stage of life. In many patients, mitochondrial disease may be an inherited condition, i.e., it runs in families (genetic), with an uncertain percentage of patients acquiring symptoms due to other factors.
TYPES OF MITOCHONDRIAL DISEASE INHERITANCE:
AUTOSOMAL RECESSIVE INHERITANCE
Autosomal recessive inheritance may be the most common of the mitochondrial disorders. Remember that we all have two copies of every gene; one from our mother and one from our father. Only one of the two genes randomly enters an egg or sperm as it is formed. One gene from both egg and sperm results in the baby having two copies of that gene. In autosomal
recessive inheritance, both parents are carriers of the defective gene, but they each have only one copy. The parents are not affected because they also have a normal copy of the same gene. If both the egg and sperm carry the defective (bad, mutant) gene, then the child will have no working (normal) copies and will thereby manifest the disorder. Autosomal recessive inherited mitochondrial disorders usually result in severe disease with infantile onset.
Therefore, there is only a 25% chance that a child will inherit the defective gene from both parents and manifest the disease; (the same percentage applies to other siblings). Fifty percent of the children will inherit the defective gene from only one parent and will become unaffected carriers (like their parents) and 25% of the children will not inherit either copy of the defective gene.
AUTOSOMAL DOMINANT INHERITANCE
With dominant inheritance, only one copy of the defective gene is required in order for the associated disorder to develop; any child that inherits the defect theoretically should manifest symptoms of the disease. Occasionally this may not occur. In children who do show symptoms of the disease, the severity can vary markedly. Both autosomal recessive and autosomal dominant inheritance are similar in regards to the highly variable manifestations of the problems caused by the defective gene. If the trait is dominant, however, there is a 50% chance of it occurring in other siblings.
MATERNAL INHERITANCE
Both male and female children inherit their mitochondrial DNA (mtDNA) only from their mother, unlike the inheritance of nuclear DNA which comes from both the mother and the father. Maternally inherited mitochondrial disorders are not rare and possibly are as common as autosomal recessive inherited disorders. All mitochondrial disorders are maternally inherited.
While each of our cells contains exactly 2 copies of virtually every nuclear gene, each cell contains varying numbers of mtDNA copies, often several thousand per cell. People with maternally inherited mitochondrial disease may have any number of defective mtDNA cells. While one might assume that the more mutant mtDNA a cell contains, the more problems it will have; actually, the cell works quite well until the proportion of mutant mtDNA reaches a threshold (which varies among different tissues and by the nature of the different mutation)s. MtDNA inheritance has a more serious prognosis for the family than autosomal inheritance since there is a 100% chance of the trait occurring in other siblings, although the effects may be more or less severe. This means that the symptoms, severity, age of onset, etc,. may vary tremendously within a family. Again, such variations could create an almost infinite number of manifestations. Unlike autosomal recessive inheritance, the onset of maternally inherited disorders is usually seen somewhat later in life, with the manifestations occurring anywhere from toddler age well into adulthood.
The combination of mtDNA and nDNA defects and their correlation in mitochondrial formation and function is as yet unknown.
The diagnosis of mitochondrial disease, at times, is extremely evasive and invasive; not to mention time and labor intensive and in most cases extremely expensive. A single muscle biopsy may cost in the range of $26,000.00, so many insurance providers refuse to reimburse for this potentially important and powerful diagnostic technique, especially when it may require multiple biopsies for a specific diagnosis to be obtained. Some doctors and/or medical centers may even be unwilling to recommend this testing, since all mitochondrial diseases are thought to
be untreatable and are lump-summed into a vague category of incurable disorders for which the only treatment options are to try to ameliorate some of the symptoms, keep the patient comfortable, and/or to perhaps delay or prevent progression of the disease. Current treatment usually involves intensive vitamin and enzyme therapies along with occupational and physical therapy. The rationale seems to be that it is not worth the time, trouble or expense to specifically identify a disease which the medical community basically has no idea how to treat. Unfortunately, from a variety of perspectives, diagnosis thereby becomes irrelevant and unnecessary. It is often due to the parents’ tenacity in pursuit of a definitive diagnosis that the more intensive tests are performed.
It is usually the “ruling-out” of the obvious simple causes of multiple, often extremely serious symptoms, that finally initiates the quest for a diagnosis of a possible mitochondrial disorder. Sometimes problems are noted by almost every doctor the child visits, i.e., neurologist, pediatrician, ophthalmologist or orthopedic specialist, etc. However, these observations may never be brought together into a coherent theory of diagnosis. It is especially true in the evaluation of the infant or child with the possible risk of mitochondrial disease that medicine should not be “cubby-holed” by specialty. I would therefore, urge all parents to discuss all aspects of their child’s health with each medical professional; mention your child’s change in vision or bowel/bladder habits to your child’s neurologist and the opthalmologist’s or gastroenterologist’s concerns to your neurolgist or pediatrician. Hopefully, by so doing you will be giving all of them all a path of discovery into your child’s problem.
Just as in any medical evaluation, diagnosis of mitochondrial disease begins simply with a family history and physical/ neurological examination of the patient. From that point, metabolic examinations will include blood, urine and spinal fluid tests (if necessary). If there is neurologic involvement, testing should include SPECT brain imaging to ascertain brain blood flow/metabolism or magnetic resonance imaging (MRI) to determine anatomic problems in the brain. Retinal or electroretinogram might be ordered for detection of a visual disorder and EKG or echocardiogram might be called for if cardiologic symptoms are present. Evoked potentials, which measure the nerve conduction from the brain back and forth to the eyes (VEP: visual evoked potentials), and the ears (BAER: brain auditory evoked response), may also need to be tested. Blood tests may be needed to determine thyroid function, and also to perform genetic DNA testing. The more invasive tests, such as biopsy of skin, muscle or brain, as earlier stated, are invasive and expensive, and are only performed as needed.
In this chapter we present one of the most complex mitochondrial disorders ever described with a totally remarkable outcome resulting from hyperbaric oxygen therapy. This is the case of little Gracie.
GRACIE
Mitochondrial cytochrome c reductase deficiency is an extremely rare condition. Only five cases ever diagnosed and cited in medical reviews worldwide could be found. Life expectancy is considered to be virtually zero. In four of the cases identified, the children died as infants (at
Categories:
HBOT for Mitrochondrial Cytopathies
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