Biology 202
1999 Final Web Reports
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Adrenoleukodystrophy and Myelin: Where's the Connection?

Emma Kirby-Glatkowski

Adrenoleukodystrophy. Also known as ALD. Ten years ago many people would not be familiar with this extremely rare childhood disease. But now awareness has increased as a result of the 1992 MCA Universal film, "Lorenzo's Oil". This true story movie shows the struggles of a family whose son is dying from this disease and their fight to try to save him and children like him. After seeing this movie myself I became very interested in ALD and the possible ways to cure or treat it. In the last decade there has been some amazing research done in conjunction with this disease and the few others who, like it, occur as a result from the breakdown or loss of myelin in the brain.

The first step in understanding adrenoleukodystrophy is to ask what it is and how it works. According to the fact sheet put out by the National Institute of Health in Bethesda, MD in 1997, "ALD is a rare, genetic disorder characterized by the breakdown or loss of the myelin sheath surrounding nerve cells in the brain and progressive dysfunction of the adrenal gland" (1). This disorder affects fatty acid metabolism which causes the dysfunction of the adrenal glands, the nervous system, and the testes (2). This leads to progressive neurological disability and death (3).

Physical symptoms include, but are not limited to, visual loss, deafness, learning disabilities, seizures, dysarthria (poorly articulated speech), dysphagia (difficulty swallowing), strabismus (crossed eyes), fatigue, disturbance in gait and coordination, vomiting, paralysis, blindness, melanoderma, and dementia (1) (2) (4). But this disease does not stop with merely physical changes, there are many behavioral changes which are particularly disturbing for parents of ALD boys. These changes include abnormal withdrawal or aggression, hyperactivity, difficulty in understanding spoken material, poor memory, and poor school performance (1) (2).

ALD has an incidence rate of 1/100,000 and strikes boys 4-8 years old (4). But why does ALD only affect boys? The answer to this question is found in genetics. This disease is famial, x-linked recessive. That is, the allele that causes it is found on the X-chromosome. Recessive traits can only be expressed if they are not paired with the dominant form. During meiosis, mothers give an X-chromosome to their children and the father will give either a Y-chromosome or an X. This determines the sex of the child. Because males only have one X-chromosome, they have a much greater chance of contracting the disease than females do. They only need one recessive allele on their X-chromosome. If the mother is a carrier she has a 50-50 chance of giving the recessive allele to her baby. Males are not carriers because any male who has the recessive allele expresses the disease and dies from it before they can reproduce. A female child would be affected by the recessive alleles if she were to have the recessive allele on each of her chromosomes. But because males do not carry the allele, it is impossible for females to receive two recessive alleles. Therefore, only male children contract ALD although there may be some symptoms and disorders associated with carrying the disease found in females as well (1).

Now that we understand a little more about how ALD is contracted we need to understand how it works in order to know how it can be treated. The myelin coating along the axons of neurons allows impulses to "jump" more quickly along the length of the axon (9). Without this insulating layer of myelin, the transmission of nerve impulses is greatly slowed. When all myelin is lost, most impulses fail to even reach their destination. With the loss of the myelin sheath the adrenal gland loses its ability to breakdown fatty acid chains in the usual manner. People with ALD accumulate high levels of saturated, very long chain fatty acids (VLCFA) in their brain and adrenal cortex because an enzyme does not break down the fatty acids in the normal manner (3). It is the accumulation of these VLCFAs and the consequent dysfunction of the adrenal glands that cause the symptoms found in ALD patients.

There are many treatments being researched now but most of them are merely symptomatical. Although there are methods for treating the symptoms caused by this dysfunction, such as steroids (cortisone and cortisol) (2) and experimental drugs (beta inferon and thalidomide) (7), there is not yet anything that can be done to treat or cure the true root of the disease, the deterioration of the myelin sheaths. Until we find a way to do this, we must continue treating ALD on a symptomatical basis. One of the most helpful treatments involves the manipulation of diet using glyceryl trioleate-trieurucate oil (Lorenzo's oil) which has been highly successful in lowering VLCFA levels, but not in affecting the rate of neurological deterioration in symptomatic patients (7). There is also an experimental procedure involving bone marrow transplants that may be of some use in the future. These treatments may ease the sufferings of victims suffering from demyelination or even delay their death, but for a treatment to be truly effective, it needs to address the regrowth of the Schwann cells that produce the myelin.

One of the most touching things about "Lorenzo's Oil" was the parent's determination to fight and conquer this disease. I was very moved by the fact that they, merely laymen in the field of medicine, were able to approach the illness scientifically and methodically to create such an effective treatment as Lorenzo's Oil. This idea is very important in today's society. Many people believe that science is merely for scientists and doctors, but in reality, anyone can act or think in a certain manner to reach the desired answers. It takes coordination, determination, and cooperation. You ask all the questions you can think of and then use the answers you find to those questions to ask more. In fact, Lorenzo's father Augusto Odone, is the president and co-founder of an organization called The Myelin Project (5). It is the hope of thousands of people that this project will provide a true treatment for diseases involving demyelination. This excerpt from their mission statement sums up their goals concerning the task at hand and their methods for creating a solution: "Behind The Myelin Project is a multinational gathering of families struck by one demyelinating disease or another. Refusing to accept the conventional view that science cannot be hurried, they resolved to advance the moment when myelin can be restored".

The Myelin Project is a non-profit organization that includes eight branches located in Italy, Austria, Switzerland, Britain, France, Germany, Spain, and Dubai. Their goal is to accelerate research on myelin repair and they have set up a Work Group from among the top international laboratories specializing in myelin repair. Research done here is both collective and cooperative. It is infinitely hopeful for patients with adrenoleukodystrophy and other disorders involving myelin loss. Because they have gathered such an extensive group of researchers who share similar ideas and beliefs concerning the practice both of medicine and research, they have been able to make progress at a very promising pace.

Some of the most recent and interesting research I was able to find came from the 1998 TMP (The Myelin Project) newsletter (6). This information was years more recent than almost anything else I could find on the web which shows what a positive influence this project is having on the scientific community. Dr. Timothy Vollmer of the University School of Medicine at Yale is doing some particularly interesting research. He has finalized a protocol for the transplantation of myelin-forming cells into humans. He plans to transplant Schwann cells into the central nervous systems (CNS) of five MS patients, each receiving two transplantations three months apart. These patients would then be treated with beta interferon which should cause remyelination. He plans to use Shwann cells from the patient's own peripheral nervous system for the transplantations which should prevent the patient's immune system from destroying them. Dr. Jeffrey Kocsis, also from Yale, has already begun the required pre-clinical studies to demonstrate the safety of the transplantation procedures in artificially demyelinated primates. Their hope is that these procedures will not be harmful to monkeys and therefore should not be harmful to humans.

Similar work is being done throughout the world using the transplantation of olfactory ensheathing cells (OECs). These cells have been able to survive cross-species transplantation and obtain significant amounts of remyelination. Others are working with human neural precursor cells which are similar to fetal stem cells. It is hoped that because these cells have yet to differentiate, they will travel to the place where myelin is needed and differentiate into cells that will regrow the missing myelin. Augusto Odone has reported that "indeed this work is now so advanced that an increasing number of neurologists and clinicians on both sides of the Atlantic believe it will soon be possible to conduct transplantation trials on myelin disease sufferers." (8)

This group of researchers and doctors has also found many new drugs to treat ALD. Lovastatin, a cholesterol lowering drug, has been observed to level off the VLCFA levels in ALD patients. Although it may be as effective as Lorenzo's Oil, it does have some side effects which are not present in patients taking Lorenzo's Oil. There have also been mixed results for 4-phenylbutyrate that seems to work well in some mice, but not humans and most other mice.

Through use of the Internet I was able to learn a lot both about adrenoleuko-dystrophy and the type of research and tests that are presently being done to learn more about it and ultimately to treat it. But what does the future hold for the victims of this disease? With the cooperative efforts of scientists and other concerned individuals in projects such as The Myelin Project, new hope has arisen. It is these people, addressing the ALD problem through scientific thinking, who will create the answer. By progressively asking questions based upon their observations they are able to grow closer and closer to the cure. They must keep an open mind and remember that in science, anything can happen. Things are almost never what you think they are.

WWW Sources

1)Adrenoleukodystrophy,

2)Adrenoleukodystrophy,

3)NCBI: Adrenoleukodystrophy,

4) ADRENOLEUKODYSTROPHY ,

5)The Myelin Project ,

6)TMP Newsletter ,

7)Virtual Hospital: Radiology Resident Case of the Week Adrenal Leukodystrophy (ALD) ,

8) Neurodegenerative Disorders of Childhood- Dr. Greene's House Calls ,

9) Metachromatic Leukodystrophy ,




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