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What is Adrenoleukodystrophy (ALD)?

Adrenoleukodystrophy, or ALD, is a genetic disease that affects 1 in 17,000 people. It is an X-linked genetic disease, which means, it most severely affects boys and men.

Adrenoleukodystrophy, or ALD, is a genetic disease that affects 1 in 17,000 people. It is caused by mutations in ABCD1, a gene located on the X chromosome. X-linked diseases most severely affect boys and men. The result is an inability to breakdown very long chain fatty acids (VLCFAs). ALD involves multiple organs in the body, but most prominently affects the brain and spinal cord. The disease destroys myelin, the protective sheath that surrounds the brain’s neurons. Without myelin, nerve cells that allow us to think and to control our muscles no longer function correctly. ALD knows no racial, ethnic, or geographic barriers.

There are different forms of ALD:

  1. Asymptomatic – patients show no signs or symptoms

  2. Adrenal Insufficiency – most patients will develop adrenal insufficiency over time

  3. Cerebral ALD – affects the brain, most often in childhood, but can also occur in adolescence and adulthood

  4. Adrenomyeloneuropathy (AMN) – begins in adulthood and affects mobility.

Unfortunately, there is no reliable way to predict how the disease will present.

What is myelin (white matter) and why is it so important in the nervous system?

Myelin constitutes the “white matter” of the brain. It consists of fatty acid molecules, and provides the protective covering of the nerve cells, similar to insulation surrounding an electric wire. Myelin is required for the rapid, precise transmission of information to and from neurons throughout the brain and spinal cord. Demyelination is the stripping away of the fatty coating (white matter) that keeps nerve pulses confined and maintains the integrity of nerve signals. This process inhibits the nerves ability to conduct properly, thereby causing neurological deficits. In childhood cerebral ALD, not only do cells undergo demyelination, but there is also an inflammatory response, all of which destroy the brain. When myelin is damaged, communication is lost during transmission. This results in the loss of voluntary and involuntary functions in the body. Currently there is no known treatment to reverse damaged myelin, although there are options to manage symptoms. Proactive, comprehensive medical care will allow families and caregivers to give the affected individual the best quality of life possible. Furthermore, through ALD Newborn Screening, affected children have the opportunity to benefit from lifesaving treatment, which can halt the disease (see Treatment Section).

What causes ALD? And why does the disease typically impact boys?

ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD Protein (ALDP). ALDP functions as a peroxisomal membrane transporter. The transporter is required for thenormal turn over, or metabolism, of a special type of fatty acids in the brain and spinal cord. Without thetransporter, the normal metabolism of fatty acids does not occur. Therefore, the brain and spinal cordundergo demyelination. Biochemically, individuals with ALD show very high levels of unbranched, saturated,very long chain fatty acids, particularly - the one that has 26 carbon chains called cerotic acid (26:0).

ABCD1 resides on the X chromosome. Boys inherit only one X chromosome, which is passed on from mom. Because boys only have one copy of the gene, when it is mutated, they become susceptible to ALD.

Girls inherit two X chromosomes, one from each parent. The functional copy inherited from dad usually protects female children from the disease. Females with the mutation are traditionally referred to as “carriers”, and can pass the abnormal X chromosome on to offspring. Importantly, the field is evolving, we are now starting to find that some women experience neurological symptoms later in adulthood. It is possible – but very rare – for girls to inherit 2 copies of the mutation from both parents.