Facts on X-ALD

March 24th, 2015 |

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

DEFINITION

Adrenoleukodystrophy (X-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 (there is no relation with “neonatal adrenoleukodystrophy” that belong to the disorders of the Zellweger spectrum). In 1971, Dr. Michael Blaw introduced the name adrenoleukodystrophy; ‘adreno’ refers to the adrenal glands; ‘leuko’ refers to the white matter of the brain, and ‘dystrophy’ means abnormal growth or development.

BIOCHEMISTRY

X-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-lipids) in tissues of the body. These VLCFA-lipids harmful for cells and tissues. For reasons that have not yet been resolved brain, spinal cord, testis and the adrenal glands are affected. In the central nervous system the buildup of VLCFA-lipids eventually destroys the myelin sheath that surrounds the nerves causing neurologic problems. VLCFA-lipids are toxic to adrenal gland cells and their malfunction causes Addison’s disease.

The ALD protein transports very long chain fatty acids.
Figure 1
While some of the VLCFA-lipids that accumulate in X-ALD come from the diet, they are largely derived from production within the body through elongation of long-chain fatty acids. The accumulation of VLCFA-lipids in X-ALD patients results from the impaired capacity to degrade these fatty acids. The breakdown of VLCFA normally takes place in a part of the cell, which is referred to as the peroxisome. All cells of the body, except red blood cells, have peroxisomes (Figure 1). Patients with X-ALD lack one of the proteins required for this degradation to take place. The protein that is missing or defective is called ALDP (X-ALD protein). ALDP is crucial for the transport of the VLCFA from the cell into the peroxisome.
X-ALD is due to mutations or defects in the gene that codes for ALDP. This gene is located on the X-chromosome and referred to as the ABCD1 gene.

Figure adapted from: Engelen, Kemp & van Geel: Van gen naar ziekte; X-gebonden adrenoleukodystrofie (From gene to disease; X-linked adrenoleukodystrophy). Ned Tijdschr Geneeskd 2008;152:804-808. With permission of the Nederlands Tijdschrift voor Geneeskunde.

EPIDEMIOLOGY

X-ALD occurs all over the world and is not limited to certain ethnicities. The incidence of X-ALD has been estimated to be 1:17.000 newborns.

GENETICS

X-ALD is an X-linked disorder, which means that the X-ALD gene is located on the X-chromosome. Women have two X-chromosomes, men only one. In women, the affected X-chromosome, the one with the defective X-ALD gene, does not manifest (or to a lesser extend) because of the presence of a normal copy of the gene on the other X-chromosome. Men have one X-chromosome and one Y-chromosome (Figure 3). When the father is the carrier of affected X-ALD gene, there is no other X-chromosome for protection; therefore he will have X-ALD.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2 (left): If a woman is a carrier for X-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 X-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 X-ALD and a 50% chance that he will be unaffected.

Figure 3 (right): For an X-linked disorder, such as X-ALD, if an affected man has children, then all of his sons will be entirely normal (he always passes his Y-chromosome to his son), but all of his daughters will be carriers (he always passes his only (affected) X-chromosome to his daughter).

CLINICAL COURSE

Patients with X-ALD are asymptomatic at birth. While all patients have a mutation in the X-ALD gene, the clinical outcome of individual patients cannot be predicted.

TESTING

X-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 X-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. A newborn screening method has been developed at the Kennedy Krieger Institute that can detect elevated VLCFA in bloodspots. In 2014, New York State expanded its newborn screening program to include X-ALD. Newborn screening allows prospective monitoring and early intervention. It is anticipated that other states and countries will follow.

RESEARCH

Extensive research on X-ALD is being done around the world. In 1993, the gene for X-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 trying to find a cure for X-ALD.

TREATMENT

There is no general curative therapy for X-ALD.

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