X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy is a disorder that occurs most often in males. It mainly affects the nervous system and the adrenal glands, which are small glands located on top of each kidney. People with this disorder often have progressive destruction of the fatty covering (myelin) that insulates nerves in the brain and spinal cord. They may also have a shortage of certain hormones caused by damage to the outer layer of the adrenal glands (adrenal cortex). This hormonal deficiency is known as adrenocortical insufficiency.

There are three distinct types of X-linked adrenoleukodystrophy: a childhood cerebral form, an adrenomyeloneuropathy type, and a type called Addison disease only.

Children with the cerebral form of X-linked adrenoleukodystrophy experience learning and behavioral problems that usually appear by the age of 10. Over time the symptoms worsen, and these children may have difficulty reading, writing, understanding speech, and comprehending written material. Additional signs and symptoms of the cerebral form include aggressive behavior, vision problems, and impaired adrenal gland function. The rate at which this disorder progresses is variable; however, total disability within several years is not uncommon.

Signs and symptoms of the adrenomyeloneuropathy type appear between early adulthood and middle age. Affected individuals develop progressive stiffness and weakness in their legs (paraparesis), experience urinary and genital tract disorders, and often show some degree of brain dysfunction. Most people with the adrenomyeloneuropathy type also have adrenocortical insufficiency.

When adrenocortical insufficiency occurs without any other symptoms it is sometimes called Addison disease. People with X-linked adrenoleukodystrophy whose only symptom is adrenocortical insufficiency are said to have the Addison disease only form. Adrenocortical insufficiency may cause weakness, weight loss, skin changes, vomiting, and coma. Most people initially diagnosed with the Addison disease only form of X-linked adrenoleukodystrophy eventually develop all the signs of adrenomyeloneuropathy by the time they reach middle age.

For reasons that are unclear, different types of X-linked adrenoleukodystrophy can be seen in affected individuals within the same family.

The prevalence of X-linked adrenoleukodystrophy is approximately 1 in 20,000 individuals worldwide. This condition occurs with a similar frequency in all populations.

Mutations in the ABCD1 gene cause X-linked adrenoleukodystrophy. The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP), which is involved in transporting molecules into peroxisomes. Peroxisomes are small sacs within cells that process many types of molecules. Inside peroxisomes, ALDP is thought to play a role in the breakdown of certain fats (very long-chain fatty acids or VLCFAs).

ABCD1 gene mutations result in a shortage (deficiency) of ALDP. When this protein is lacking, the breakdown of very long-chain fatty acids is disrupted, causing abnormally high levels of these fats in the body. The accumulation of very long-chain fatty acids may be toxic to the adrenal cortex and the myelin membranes that surround many of the nerves in the brain and spinal cord.

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all.

Many females who carry one altered copy of the ABCD1 gene do not have any features of X-linked adrenoleukodystrophy; however some females with one altered copy of the gene have medical problems associated with this disorder. The signs and symptoms of X-linked adrenoleukodystrophy tend to appear at a later age in females than in males. In affected women, the disorder is usually similar to the adrenomyeloneuropathy type, although it may occasionally impair adrenal gland function. Less commonly, affected females have signs of the childhood cerebral form of this condition.