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The Human and Scientific Story of Adrenoleukodystrophy

by 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.

References

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