Dr. Inderjit Singh

Researchers have identified several different compounds that can reduce the buildup of a harmful substance in cultured skin cells from boys with the gene defect that causes adrenoleukodystrophy, or ALD. The compounds also stop the production of inflammatory chemicals in brain cells from rats, suggesting that they may eventually prove useful in treating the neurological symptoms of ALD.

The cholesterol-lowering drug lovastatin is one of the first substances shown to reduce inflammatory compounds as well as lower the harmful levels of very long-chain fatty acids (VLCFAs) in cultured cells from boys with ALD. The studies, performed by Inderjit Singh, Ph.D., professor of pediatrics, and his associates, Kalipada Pahan, Ph.D. and Mushfiquddin Khan, Ph.D., are reported in the June issue of the “Journal of Lipid Research” and the April issue of the journal “FEBS” (Federation of European Biochemical Societies) Letters.

ALD is a rare, X-linked genetic disorder that occurs in one of every 25,000 to 30,000 boys. There are three different forms of the disease, all caused by the same defective gene. The most severe form, depicted in the movie, “Lorenzo’s Oil,” usually appears between the ages of four and eight and leads to death in two to three years. Other, less severe forms occur later in life and are known as adrenomyeloneuropathy (AMN) and Addison’s disease.

ALD causes progressive damage to myelin, a fatty membrane covering that insulates nerve fibers in the brain and spinal cord, and to the adrenal glands. This damage is probably due to inflammation, says Singh. The genetic defect in ALD makes it impossible to produce one of the body’s normal proteins and causes a buildup of VLCFAs within cells, although how this buildup leads to the deterioration associated with the disease is not clear.

While several therapies for ALD are already being tested, “these therapies have not been effective in stopping the steady deterioration that characterizes the disorder,” says Singh. Bone marrow transplantation, dietary manipulation, and the compound glycerol trioleate-trierucate oil (or “Lorenzo’s oil”) all reduce the level of VLCFAs in children with ALD, but do not consistently reduce the neurological symptoms. Hormone therapy can replace missing adrenal hormones, but does not affect neurological symptoms. Since the gene that is defective in ALD has been identified, gene therapy may eventually become available for the disease. However, it will probably take several more years to develop this type of therapy for ALD.