Facts on ALD

April 15th, 2016 |

Marc Engelen, M.D. and Stephan Kemp, Ph.D

Definition

Adrenoleukodystrophy (ALD) is a serious progressive, genetic disorder that affects the adrenal glands, the spinal cord and the white matter of the nervous system. It was first recognized in 1923 and has been known as Schilder’s disease and sudanophilic leukodystrophy. In 1970, the name adrenoleukodystrophy was introduced; ‘adreno’ refers to the adrenal glands; ‘leuko’ refers to the white matter of the brain, and ‘dystrophy’ means abnormal growth or development. There is no relation with “neonatal adrenoleukodystrophy” which belongs to the peroxisomal biogenesis disorders of the Zellweger spectrum.

Biochemistry

ALD is an inherited metabolic storage disease whereby a defect in a specific enzyme results in the accumulation of very long-chain fatty acids (VLCFA) in all tissues of the body. These VLCFA are harmful for cells and tissues. For reasons that have not yet been resolved brain, spinal cord, testis and the adrenal glands are primarily affected. In the central nervous system the buildup of VLCFA eventually destroys the myelin sheath that surrounds the nerves causing neurologic problems. VLCFA are toxic to adrenal gland cells and their malfunction causes Addison’s disease (adrenal insufficiency).

The ALD protein transports very long chain fatty acids.

Figure 1: VLCFA that accumulate in ALD are mainly produced in cells from elongation of long-chain fatty acids. To maintain the tight balance in VLCFA homeostasis, excess amounts of VLCFA have to be degraded. VLCFA can only be degraded in peroxisomes. All cells of the body, except red blood cells, have peroxisomes. ALD is caused by mutations in the ABCD1 gene that produces the ALD protein (ALDP). ALDP functions as a transporter of VLCFA from the cytosol into the peroxisome. A deficiency in ALDP blocks this transport, which results in impaired degradation of VLCFA and a subsequent buildup of VLCFA in cells, tissues and organs. The enzymes that are required from the breakdown of VLCFA are present within the peroxisomes, but the VLCFA cannot reach them.

Epidemiology

ALD occurs all over the world and is not limited to certain ethnicities. The overall incidence of ALD is about 1 in 17.000 newborns.

Genetics

ALD is an X-linked disorder, which means that the ALD gene (ABCD1) is located on the X-chromosome. Men have one X-chromosome and one Y-chromosome (XY; Figure 2). When the father is the carrier of affected ALD gene, there is no other X-chromosome for protection; therefore he will have ALD. Women have two X-chromosomes (XX; Figure 2). Women that carry the defective gene are referred to as carriers. In the past it was thought that only a small percentage of carriers developed clinical symptoms. It is now clear that that this is not true (see below and the Clinical presentations page). The clinical symptoms in women are somewhat milder than in men. But 80% of women with ALD do develop clinical symptoms. Therefore, ALD carriers should be considered ALD patients (women with ALD). The most likely explanation for women with ALD to develop a milder form of the disease is the presence of a normal copy of the ABCD1 gene on the other X-chromosome. In women, in each cell one of the X-chromosomes is inactivated. This is a random process throughout all the cells of the body. It is thought that the presence in tissues and organs of cells that express the healthy copy of the ABCD1 gene protects women with ALD from developing the brain variant (cerebral ALD).

Figure 2: (Left) If a woman is a carrier for ALD she has the following possible outcomes with each newborn: when the child is a daughter, there is a 50% chance that the daughter is a carrier for ALD and a 50% chance that the daughter is unaffected. In case the child is a boy, there is a 50% chance that the son has ALD and a 50% chance that he will be unaffected. (Right) For an X-linked disorder, such as ALD, if an affected man has children, then all of his sons will not have the disease (he always passes his Y-chromosome on to his son). But all of his daughters will be carriers (he always passes his only (affected) X-chromosome on to his daughter).

Figure 2: (Left) If a woman is a carrier for ALD she has the following possible outcomes with each newborn: when the child is a daughter, there is a 50% chance that the daughter is a carrier for ALD and a 50% chance that the daughter is unaffected. In case the child is a boy, there is a 50% chance that the son has ALD and a 50% chance that he will be unaffected. (Right) For an X-linked disorder, such as ALD, if an affected man has children, then all of his sons will not have the disease (he always passes his Y-chromosome on to his son). But all of his daughters will be carriers (he always passes his only (affected) X-chromosome on to his daughter).

Clinical course

Patients with ALD are pre-symptomatic at birth. Although all babies born with ALD have a mutation in the ABCD1 gene, the clinical course of an individual patient remains entirely unpredictable, even among family members who share the same mutation.

Testing

ALD/AMN is diagnosed by a simple blood test, which is analyzed for the amount of very long-chain fatty acids. This test is accurate in males. However, in about 20% of women with ALD the VLCFA test shows normal results and thus gives a “false negative” result. A DNA-based blood test is available. This test permits accurate identification of carriers by genetic testing, and if it is normal can assure a woman that she is not a carrier. Diagnostic testing, carrier screening and prenatal diagnosis are available.

Newborn screening

A newborn screening method has been developed. It can detect elevated VLCFA (as C26:0-lysoPC) in bloodspots. In 2014, New York State started newborn screening for ALD. In 2015, the Netherlands expanded its newborn screening program from 17 to 31 conditions, including ALD. In February 2016, ALD was added to the United States Recommended Uniform Screening Panel (RUSP). Early diagnosis of ALD is the key to saving lives, because newborn screening allows prospective monitoring and early intervention.

Research

Extensive research on ALD is being done around the world. In 1993, the gene for ALD was identified through the combined efforts of Drs. Patrick Aubourg and Jean-Louis Mandel in France and Dr. Hugo Moser in the U.S. This has opened new doors for further study. Research activities are focused on many aspects, to answer fundamental questions, like: “How do the VLCFA eventually result in the loss of myelin?”; “Why does one patient develop cerebral ALD while another (which can even be the patient’s brother) develops AMN at a later age?”, as well as the development of a cure for ALD.

Treatment

There is no general curative therapy for ALD.

A 10 minute overview of ALD


Produced by Youreka Science in collaboration with ALD Connect, Inc.
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