What is Adrenoleukodystrophy?

Adrenoleukodystrophy (ALD) is a rare inherited disease affecting young boys. The disease typically first causes behavioral problems starting at 6-8 years old. Frequently, the children are misdiagnosed as having attention deficit disorder with hyperactivity. As the disease progresses, cognitive skills start to decline rapidly. Tragically, most children die from ALD within 5 years of diagnosis.

Two tissues are primarily affected by the disease, as the name, adrenoleukodystrophy, indicates: adreno for the adrenal glands and leuko for the white matter of the brain. The adrenal damage can usually be controlled by hormone therapy, but there is currently no treatment for the destruction of the white matter. It is the loss of the white matter that is responsible for the behavioral issues and the subsequent cognitive decline later in the disease.

The gene that causes ALD has been identified. It is called ABCD1, as it is a member of a protein family known as the ABC-transporters. The ABC-transporters have a diverse range of functions within the cell and their mutations cause a variety of diseases. For example, cystic fibrosis is caused by mutations in the ABCC7 gene. The ABCD1 gene, which causes ALD, is found in the peroxisome of cells. The peroxisome is an intracellular structure whose function is to detoxify cellular waste products, and to break down fatty acids.

The function of ABCD1 seems to be essential for the breakdown of specific fatty acids, as they accumulate in affected tissues. Why the accumulated fatty acids are particularly toxic to the adrenal glands and the white matter is unknown.

There is another mystery to the ALD story. Only about 50% of boys with a mutant form of ABCD1 develop ALD. The rest develop a different disease, adrenomyeloneuropathy (AMN) in the second or third decade of life. In AMN, the white matter appears normal, but the neurons in the spinal cord start to degenerate. The loss of spinal neurons leads to severe muscle weakness, but the learning abilities of patients with AMN are normal, and they typically have a normal life span. It is currently impossible to predict which children will develop ALD and which AMN. In fact, identical twins have been described in which ALD is present in only one of the children.

Adrenoleukodystrophy Research at the MGH

1. We are interested in defining the factors that determine the fate of a patient with mutations in the ABCD1 gene. Should we be able to control the circumstances that lead to AMN, we may be able to dramatically decrease the risk of ALD.

We have recently identified a family that has only developed AMN over 6 generations, with no cases of ALD being reported. To our knowledge, this family is unique in having only AMN and never ALD. Unusually, all the women in this family are also affected. This family carries a mutant form of ABCD1, but the mutation is an unusual type of genetic change; a deletion of a very small segment of DNA.

The segment of DNA lacking in these patients includes a key signal for the normal creation of protein from the ABCD1 gene. The normal sequence of events leading from DNA to protein synthesis is as follows. A copy of DNA is transcribed into RNA. That RNA sequence includes the instructions for the protein synthesis. There is a signal imbedded in the RNA that indicates where the protein translation is to start.

In this family, such a signal is missing for ABCD1; however, an ABCD1-like protein is still translated. How this protein is being synthesized and how it functions are key questions in understanding the how this family's disease is different than typical ALD. And, as noted above, understanding these issues may indicate an approach to decreasing the risk of ALD in other families.

2. We are interested in defining factors that increase the disease incidence in the females of this family. One possible explanation resides in understanding the X-chromosome. The disease gene resides on the X-chromosome, which is why it typically affects only males. Females, which have two X-chromosomes, will most likely have one normal and one mutant form of the gene. However, in any given cell, only one of the X-chromosomes functions, while the other is silenced. In this family, it appears that the normal X-chromosome is silenced, instead of the mutant one. If we can alter the silencing, then the women in this family should be protected from the disease.

3. We are interested in developing a mouse model for AMN. Such a model would provide tissues and resources with which to understand the biology of the disease. While human studies are important, there are experiments that simply cannot be done with out a mouse model. For example, the disease process can be studied at almost any stage of the progression in a mouse. Furthermore, a mouse model is critical for therapeutic development. Using a mouse model, we can develop screens for potential drugs. And once potentially useful chemicals are identified, we can test them in the mice. This is an important step in evaluating whether or not drugs should be administered to humans in a clinical trial.