The Human and Scientific Story of Adrenoleukodystrophy

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Biology 202
2000 First Web Report
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The Human and Scientific Story of Adrenoleukodystrophy

Anna Arnaudo

At the age of five, a normally happy, well-behaved Lorenzo Odone began to have problems focusing in school and controlling his emotions. Testing revealed that Lorenzo had childhood cerebral x-linked adrenoleukodystrophy (ALD), a rare, basically ignored genetic demyelinating disease that shows symptoms between the ages 5 and 12 (3). A diagnosis of ALD was equivalent to a death sentence; typically death ensued within a few years (5). Lorenzo's parents, Michaela and Augusto, were not willing to lose their son without a fight. They began to investigate the disease on their own and worked towards bringing demyelinating diseases to the forefront of scientific research.

ALD is one of eight leukodystrophies, inheritable metabolic diseases that lead to the destruction of myelin. The disorder is a recessive X-linked genetic mutation, meaning that the trait is carried on the X chromosome. As a result of X-linkage, the disease only affects males. Affected men do not live long enough to pass the gene on to their offspring. Since females pass on the sole X chromosome obtained by male offspring, the trait has to be inherited from the mother. The single gene mutation responsible for this disease is found at locus Xq28 (2). This gene mutation causes the production of a malfunctioning transporter protein found in peroxisomes, an entity within cells responsible for breaking down long chain fatty acids. Without the use of this protein, the enzyme very long chain fatty acid CoA synthetase cannot pass into the peroxisomes. In the absence of this enzyme, very long chain saturated fatty acids (VLCSFAs) that are shipped into peroxisomes cannot be broken down. VLCSFAs are fatty acids that do not contain carbon-carbon double bonds and are 24 or 26 carbon molecules in length (3). An inability to break down VLCSFAs leads to their accumulation within the body, particularly within the white matter of the central nervous system, adrenal gland, and leukocytes (blood cells) (4).

The build up of VLCSFAs is what causes the demyelination of cells within the nervous system. The way these accumulated VLCSFAs lead to the break down of myelin is not known for sure; it could possibly be that an accumulation within the myelin elicits an immune response that leads to its destruction or that myelin becomes soluble within the accumulated VLCSFAs (3). Myelin is essential to the working of both the central and peripheral nervous systems; it serves to insulate the axons of neurons and speed nerve impulses sent along axons. Without myelin, these impulses are severely slowed or stopped altogether (5). As VLCSFAs continue to accumulate within the body, more myelin continues to be destroyed and the illness progresses. Initial symptoms of the disease include crossed eyes, hyperactivity, aphasia (inability to understand verbal communication), decreased fine motor control and muscle spasms. As the disease progresses, the symptoms become more severe; these include blindness, hearing loss, paralysis, inability to speak, and dementia (6).

In the first attempt to cure Lorenzo, the Odones created a diet low in VLCSFAs to combat accumulation. However, his body continued to synthesize VLCSFAs. In order to halt demyelinization, it was necessary to impede VLCSFA synthesis. The Odones came upon a paper stating that an increase in the presence of oleic acid, a short chain unsaturated fatty acid, leads to a decrease in VLCSFA levels. With this knowledge, Augusto determined that the synthesis of very long chain unsaturated fatty acids are in competition with the synthesis of VLCSFAs. Both synthesis mechanisms compete for the use of a single enzyme. Increasing the amounts of unsaturated fatty acids available for synthesis allows for the synthesis of unsaturated fatty acids to out compete the synthesis of VLCSFAs. Interestingly, the damage to myelin is done specifically by saturated fatty acids. Unsaturated fatty acids, fatty acids that contain carbon-carbon double bonds, are not deleterious to myelin and therefore do not cause the development of ALD. The mixture of oleic acid and euric acid, another short chain unsaturated fatty acid, is referred to as Lorenzo's Oil (3).

Lorenzo's Oil is the most well known treatment of ALD, but it is not perfect. Although it was able to bring Lorenzo's VLCSFA levels down, there seems to be evidence indicating that it is not capable of stopping the progression of ALD once the disease has begun. Some researchers believe this could be due to the fact that once the initial build up has begun an immune response is triggered which continues to destroy myelin even in the absence of VLCSFAs. Studies show that Lorenzo's Oil works best as a preventative measure; one done by HW Moser indicates that if Lorenzo's Oil is administered before onset, the symptoms are greatly reduced or erased all together (7). Due to the known location of the gene and to advancements in genetics, it is possible to screen individuals for ALD long before the presence of symptoms. Another problem is that even if Lorenzo's Oil were capable of preventing the further breakdown of myelin, it is not capable of remyelinating the damage axons.

While working towards a cure for ALD, the Odones found that scientific research is often competitive and slow. Researchers do not cooperate enough to quickly solve problems such as developing methods to remyelinate neurons. In the hopes of speeding up the possibility of myelin regeneration, the Odones set up the Myelin Project. The Myelin Project is a multinational organization that funds research, brings together researchers from all over the world to discuss their progress, and allows for interactions between scientists and laypeople affected by demyelinating diseases. The involvement of laypeople provides motivation to researchers by reminding them about the important impact their research could have on so many lives (5).

With the help of the Myelin Project, some significant accomplishments have been made toward the goal of remyelination. Myelin sheaths around axons are created when glial cell membrane processes wrap themselves multiple times around an axon. There are different types of glial cells within the nervous system; Schwann cells produce myelin sheaths in the peripheral nervous system (PNS), while oligodendrocytes synthesize myelin sheaths in the central nervous system (CNS) (8). Experiments dealing with both cats and rodents show that despite the fact that Schwann cells are in the PNS they are capable of remyelinating the CNS. Researchers are currently capable of removing healthy Schwann cells from human nerves. Techniques to collect greater numbers of intact Schwann cells are being studied in hopes that a human trial of transplantation will soon occur. The Myelin Project has already obtained permission for such a trial, yet before proceeding the researchers must be able to remyelinate monkey brains. A team led by Dr. Baron-Van Evercooren has had some initial success with this by transplanting the monkey's own Schwann cells into its CNS; they are now working on verifying their first attempts. There is also research looking into transplanting oligodendrocytes. Researchers have been able to generate cultures of oligodendrocyte precursors with hopes of culturing them in large enough numbers to transplant (1).

Another area of research is looking into neural stem cells, self-renewing cells that can develop into various neural cells. They are very promising because they respond to local signals from the CNS, which tells them where to go and what to differentiate into. Since they are self-renewing, they could provide an endless supply of myelin for the CNS. It has also been found that cerebrospinal fluid can transport myelin-synthesizing cells to various parts of the CNS. Injecting neural stem cells into the cerebral spinal would therefore provide an agent of remyelination for the entire CNS; this is a forthcoming area of research (1).

The research conducted thus far indicates that remyelination of the human central nervous system is possible in the near future. The cures for leukodystrophies like ALD appear to be on the horizon. The cooperation of the researchers and volunteers at the Myelin Project is largely responsible for the success of efforts oriented toward myelin regeneration. The story of ALD is one of a tragic illness, cooperation, and science; it stands as an example for how science should work. Both the scientific and human successes gained by those working on ALD seems to bode well for even larger problems, perhaps even those involving spinal cord injury.

 

WWW Sources

1)The Myelin Project. The November 1999 Report

2)'ALD: A Case Study Using the Film "Lorenzo's Oil."'

3) A Biological Understanding of the Movie "Lorenzo's Oil"

4) Archives of Neurology. X-linked Adrenoleukodystrophy.

5) The Myelin Project Introduction

6) Healthanswers.com- Adrenoleukodystrophy

7) New Journal of Medicine- The Efficiency of Lorenzo's Oil

8) Archives of Neurology. Pelizaeus-Merzbacher Disease and Myelin

 

 

Continuing conversation
(to contribute your own observations/thoughts, post a comment below)

09/03/2005, from a Reader on the Web

I commend you on your everending struggle to find a cure. I have Multiple Sclerosis, been diagnosed 10 years ago. It is slowly progressing but I used my diagnosis to inspire me to get a degree in medicine. I am a student from the US studying in Belgrade, Yugoslavia. This month I am to graduate then shall return to the US to pass my boards so that I may be "Doctor of Medicine" back home. I hope to be involved in research of demyelinating diseases. Who better to find a cure than one who has to live and struggle with its difficulties? I am so glad to know that there is a WORLDWIDE organization successfully working together to discover the cure. May God bless and guide you in your quest. Please don't give up in your research for you give us hope for a better, healthier future.

 


Additional comments made prior to 2007
Please continue your research. I watched Lorenzo's oil when it came on t.v. I think I had been diagnosed with m.s. a few yrs earlier. At the time I remember having great hope for the future. For some reason I had it in my mind at that time a way to remylenate would be discovered in about 5 yrs. Well that has been a long time ago. I have had m.s. since 1989. Diagnosed in 1994. I am thankful to know that you are still working on the project. You are clearly wonderful people. I wish that you will be able one day to restore your sons CNS. You give people like me hope. It means more than words can ever say. May God bless and be with you through all your trials and tribulation ... Donna Lawson, 5 February 2006

Comments

Serendip Visitor's picture

Demyelination Linkages Between Disorders

So many disorders, diseases, ALD, ALS, MS, more, with one common debilitating factor - demyelination. Can all the mechanisms found in the separate studies of each be linked? Might the cures for all be contained in knowledge already gained, yet unrecognized as parts of the whole answer?

Seren's picture

Lorenzo oil

What is Lorenzo oil. My son died of ALD. My daughter has same problem. Very high vlc. Needs help

Seren's picture

What is Lorenzo oil

My son died of ALD in 2001 at the age of eleven. My daughter has the same thing. Her vac is very high. I am very concerned and worried. I want to know more about Lorenzo oil.

Adam Mincey's picture

AMN

I'm a 37 y/o man with the adult-form of ALD, Adrenomyelineuropathy (AMN). I was diagnosed at 19, but was asymptomatic. My brother, ten years my junior, was symptomatic, and was dx'd shortly before I was. Ironically now, he is healthy & asymptomatic, yet I have difficulty walking, poor balance, chronic pain & fatigue, sexual dysfunction, and other ailments. My brother and I both have Addison's, controlled with corticosterioids. Our mother who passed this to us began showing symptoms later in life. It led to her having strokes & TIA's, becoming disabled to the point of being bedridden, and finally, this past August, it ended her life. Although I am disabled and cannot work b/c of AMN, my mortality never really concerned me...until now, of course. This damned disease for me has gone from an inconvenience, to painful, to disabling, and, in my Mother's case, to fatal. I understand stem cells cannot work for advanced stages and can even worsen it. Does anyone know of ANY types of treatment out there? On a thankful note to close, I am a few years older than Lorenzo Odone. They barely were able to slow his in time to save his life. (I'm going from the movie.) If I had been affected as he was, I probably wouldn't have survived. God is good! Thank you for reading.

Serendip Visitor's picture

Oleic Acid or CoQA? Or both?

I am very interested in anything that is so devastating and has no cure. I am a pharmacist; however not a clinical pharmacist so I must still "research" a lot in order to make sense of certain entities. 23yrs of retail pharmacy; watching as people came and went (died) after getting to know them so well and see the progression of their individual states has left me wondering why something like ALD after so many years has no cure. Somewhere in the paper I read CoA helped myelin to regrow. If this is true, why do they not have on the WWW any research on that promise? What about loading up on the Coenzyme A somehow? Why hasn't stem cell research figured something out to delete or replace that enzyme so that it can get into peroxisomes; or to work in it's place? There has to be a way to get "the enzyme very long chain fatty acid CoA synthetase (to) pass into the peroxisomes". Or to find a replacement protein for the assumed malfunctioning one. Please be sure to know there are a lot of us who would gladly contribute to any research as needed; up to and including research, speaking or giving of our own myelin if it came to that. If cloning can happen in a laboratory, why can we not duplicate the myelin sheath to be tried on either monkey or human?

Luke Kleveland's picture

Lorenzo's Oil

I enjoyed this movie very much so. It was inspiring, and I'm very moved by the parent's motivation.

Anonymous's picture

This is the best page out

This is the best page out there for ALD research.

Anonymous's picture

project

I'm doing a project and this helped me a lot, thank you.

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