Facts on X-Linked Adrenoleukodystrophy (X-ALD)

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) in tissues of the body, especially the brain and the adrenal glands. Ultimately the myelin sheath that surrounds the nerves is destroyed causing neurologic problems, and the adrenal gland malfunction causes Addison's disease.

Figure 1 While some of the VLCFA that accumulate come from the diet, they are derived mainly from production within the body through elongation of long-chain fatty acids. The accumulation of VLCFA in X-ALD patients results from the impaired capacity to degrade these fatty acids. The break down 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 (Figure 2). 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. For more information on the biochemistry of X-ALD please follow this link. 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.

Figure 2 Microscopic image of a human skin cell stained with a dye that recognizes peroxisomes; they are indicated as the small green dots. In a normal situation, VLCFA are degraded in peroxisomes. In X-ALD, however, the VLCFA can not enter the peroxisomes due to a defect in ALDP that transports VLCFA from to cell into the peroxisome.

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 genetic abnormality involves the X-chromosome. Women have two X-chromosomes, men only one. In women, the affected X-chromosome, the one with the gene for X-ALD (Figure 3, red chromosome), does not manifest because of the presence of a normal copy of the gene (black chromosome) on the other X-chromosome. Men have one X-chromosome and one Y-chromosome (Figure 4). In men who have an X-chromosome for X-ALD, there is no other X-chromosome for protection; therefore symptoms may be seen in the male. For more information on genetics, mode of inheritance and genetic counseling, follow this link.

Figure 3: 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 4: For a sex-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 X-chromosome to his daughter).

CLINICAL COURSE

CHILDHOOD CEREBRAL ALD (CCALD or CCER): X-ALD can present in several forms. The classic childhood form is the most severe usually affecting boys between 4 and 10 years of age. Approximately 35% of patients with X-ALD develop this severe form of the disease Initial symptoms can be problems with concentration and learning, behavioral change, impaired vision and hearing, coordination or gait difficulties. Symptoms are rapidly progressive and lead to severe disability with spastic paraparesis (weakness of the arms and legs), swallowing difficulties and impaired consciousness. Death frequently occurs within 2 to 4 years after symptom onset due to complications such as pneumonia. Impaired adrenal function, which occurs frequently in combination with the neurological symptoms, may cause increased skin pigmentation (Addison's disease). The adrenal insufficiency can be managed by hormone replacement therapy. It is, however, the nervous system involvement, which causes the main disability and which researchers are striving to understand and treat. The prognosis of untreated CCALD is poor, usually causing severe disability and death within 2 to 4 years.

ADRENOMYELONEUROPATHY (AMN): AMN is the most common form of X-ALD. Virtually all patients with X-ALD who reach adulthood develop AMN, usually in the third or fourth decade. The spinal cord and peripheral nerves are affected causing varying degrees of difficulty with walking due to spasticity, sphincter disturbances causing incontinence for urine and feces and impotence. The disability is progressive, usually causing wheelchair dependence in decades. Life expectancy of AMN patients is normal, unless patients additionally develop cerebral demyelination, which is the case for about 20% of AMN patients. In that case, the progression and outcome will be similar as seen in the childhood form. Approximately 70% of AMN patients also have Addison's disease and/or testicular insufficiency.

ADDISON-ONLY: Primary adrenocortical insufficiency (Addison's disease) without evidence for nervous system involvement occurs in 10% of X-ALD patients (“Addison only” phenotype). However, in most patients neurological symptoms eventually occur.

CARRIERS: Female carriers can develop AMN like symptoms, although this has not been systematically studied. Clinical manifestations are usually limited to progressive paraparesis (a partial paralysis of the legs), moderate sensory loss, and peripheral neuropathy. Cerebral involvement is rare and adrenal function is almost always intact. For more information on female carriership of X-ALD, follow this link.

TESTING: X-ALD/AMN is diagnosed by a simple blood test, which is analyzed for the amount of very long-chain fatty acids. While the test is accurate in males, in about 20% of women who are proven carriers, the 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 very small volumes of blood. Work is now underway to test large sample series to confirm the sensitivity and specificity and to establish the assay as a good way to screen all newborn children for X-ALD. For much more information on diagnosis, follow this link.

RESEARCH: Extensive research is being done around the world in X-ALD. 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 CCALD 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.

• Adrenal steroid replacement therapy is mandatory for those patients that have adrenocortical insufficiency (Addison's disease), and may be life saving, but it has no effect on neurological symptoms.
• Hematopoietic stem cell transplantation (HSCT) has been demonstrated to be successful in arresting disease progression in a small subset of young, pre-symptomatic patients with demonstrable early signs of cerebral demyelination.
• Lorenzo’s oil does not alter the clinical progression of patients with neurological symptoms, but it may have a partial preventive effect in asymptomatic boys whose brain MRI is normal and who normalized their plasma VLCFA using Lorenzo's oil. To finally answer the question whether Lorenzo’s oil can be beneficial to X-ALD, a proper placebo-controlled clinical trial is ongoing at the Kennedy Krieger Institute.
• Lovastatin was demonstrated to have an effect on VLCFA. This finding, however, could not be reproduced by others. Later experiments showed that statins had no effect on brain and adrenal VLCFA levels in X-ALD mice, and even caused accumulation of VLCFA in these tissues. Because of these conflicting results, a randomized double-blind placebo-controlled clinical trial to test the effect of lovastatine as a VLCFA lowering therapy for X-ALD has been performed at the Academic Medical Center in Amsterdam. The results and conclusions have been published in the New Engeland Journal of Medicine (Engelen et al, 2010). The authors demonstrate that lovastatin treatment results in a small decrease in plasma VLCFA, but it has no effect on VLCFA levels in red and white blood cells. For more details, please follow this link.
•Drs Nathalie Cartier and Patrick Aubourg and colleagues (Saint Vincent de Paul Hospital, Paris, France) have successfully treated two 7-year old boys with early signs of cerebral ALD using gene therapy (Cartier et al. 2009). Brain MRI scans and cognitive tests showed that progression of the cerebral disease stopped after 14-16 months. For more details, please follow this link.

Last update: 04-Feb-2010