X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is caused by a variation (mutation) in the ABCD1 gene. This __gene provides instructions to make a protein called the adrenoleukodystrophy protein (ALDP). ALDP normally moves a type of fat molecule called very long-chain fatty acids (VLCFA) into a special part of the cell to be broken down. When the ABCD1 gene is changed, there is too little ALDP in the cells or the ALDP that is made does not work normally. This causes VLCFA to build up in the body. High levels of VLCFA are thought to be damaging to the outside of the adrenal glands (adrenal cortex) and the fatty covering (myelin) that surrounds the nerve cells in the brain and spinal cord. Researchers believe the damage caused by VLCFA may involve inflammation, especially in the brain.

X-linked adrenoleukodystrophy (X-ALD) is suspected when a doctor observes signs and symptoms of the disease. X-ALD should be considered as a possible cause of symptoms in four situations:

• Boys with attention deficit disorder (ADD) who also have signs of neurological problems
• Young men with progressive trouble walking or coordinating movements
• All males with adrenal insufficiency (Addison disease), even in the absence of other symptoms
• Adult women with progressive muscle weakness or wasting

If a diagnosis of X-ALD is suspected, a blood test of very long-chain fatty acids will detect elevated levels in 99% of males. Genetic testing can be used to confirm the diagnosis. After diagnosis, a brain MRI can be completed to determine the extent of the disease. A brain MRI will be abnormal even if symptoms of the disease are not very severe.

X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner. This means that the ABCD1 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes. Each woman has two X chromosomes, and each man has one X chromosome and one Y chromosome. Because men have only one X chromosome, they only have one copy of the ABCD1 gene. If this gene has a disease-causing change, they will have X-ALD.

Women who have disease-causing changes in one copy of the ABCD1 gene are known as carriers of the disease. About 80% of carriers do not have signs or symptoms of X-ALD because they have another working copy of ABCD1. However, about 20% of female carriers have symptoms that are similar to the adrenomyeloneuropathy (AMN) type of X-ALD.

If a male is diagnosed with X-ALD, it is likely that his mother is a carrier of the disease. However, about 5% of cases of X-ALD are caused by a new genetic change (de novo) in the individual. In these situations, the mother is not a carrier of the disease, and other family members are not at risk to have children with X-ALD. Therefore, when a male is diagnosed with X-ALD, it is important to determine if his mother is a carrier by testing her VLCFA levels or by genetic testing.

If a woman is found to be a carrier of X-ALD, for each of her children there is a 50% chance that he or she will inherit the change in ABCD1. This means that for each son, there is a 50% chance that he will be affected with X-ALD. For each daughter, there is a 50% chance that she will be a carrier of the disease like her mother.

X-ALD shows a characteristic known as variable expressivity. This means that the exact symptoms of each person with X-ALD can differ, even within the same family. For example, some boys may have the childhood cerebral form of X-ALD, while other members of the same family may have the adrenal insufficiency- only type. It is not known what causes variable expressivity of the disease to occur. The symptoms cannot be predicted by levels of VLCFA or by looking at the exact genetic change (mutation) in each individual.

The long-term outlook for people affected by X-linked adrenoleukodystrophy (X-ALD) depends on the exact type of the disease that each person has. The childhood cerebral form of the disease is progressive. Boys with this form of the disease often pass away within a few years of beginning to show symptoms. The other forms of X-ALD are less severe. The disease for these individuals may be slowly progressive, or it may not affect a person’s lifespan at all.

It is important to remember that the exact signs and symptoms of a person with X-ALD cannot be predicted by the signs and symptoms of other members of the family. Therefore, the long-term outlook for individuals who have X-ALD within the same family can be very different.

The treatment for X-linked adrenoleukodystrophy (X-ALD) depends on the signs and symptoms present in each person and may include:

• Corticosteroids in case of adrenal insufficiency, which are used to normalize hormone levels.
• Physical therapy that may be helpful for men with the adrenomyeloneuropathy (AMN) form of the disease.
• Bone marrow transplant, which is only recommended for boys who have brain involvement showed by brain MRI, but who have only minimal neurological or psychological findings, and who have normal clinical neurologic examination. This treatment have many risks and it is not recommended in cases of severe neurologic symptom.
• Lorenzo’s oil, recommended for boys who do not yet have symptoms of X-ALD. However, this treatment is experimental, and the treatment's exact benefit has not been definitively shown, but it may slow down the progression of the disease.

Clinical trials investigating treatment with gene therapy are currently underway and have shown some preliminary success.