March 24th, 2015 |
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.
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.
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.
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.
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).
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.
- Adrenal insufficiency (Addison-only): Adrenal insufficiency (or even a life threatening Addisonian crisis) can be the presenting symptom of X-ALD in boys and men, years or even decades before the onset of neurological symptoms. A study on neurologically asymptomatic boys with X-ALD, showed that 80% of these boys already had impaired adrenal function at the time of diagnosis of X-ALD.
- Adrenomyeloneuropathy (AMN): AMN is the most frequent phenotype of X-ALD. Virtually all male patients with X-ALD who reach adulthood develop AMN, typically between the age 20-30 years. Symptoms are limited to the spinal cord and the peripheral nerves. Initially, the neurologic disability is slowly progressive. The diagnosis of AMN is rarely made during the first 3–5 years of clinical symptoms, unless other cases of X-ALD have been identified in the same family. AMN males develop progressive stiffness and weakness of the legs, impaired vibration sense in the lower limbs, sphincter disturbances and impotence. A retrospective study revealed that AMN patients have a high risk of developing the cerebral demyelinating form of the disease before the age of 50 years. The prognosis of these patients is as poor as in cerebral-ALD patients. Approximately 70% of AMN patients have adrenocortical insufficiency and/or signs of testicular insufficiency. AMN patients frequently have scanty scalp hair that often develops during adolescence.
- Cerebral-ALD (childhood, adolescent and adult): The cerebral phenotypes are the most rapidly progressive and devastating phenotypes of X-ALD. A newborn male patient has a 35–40% risk to develop childhood cerebral-ALD between the ages of 4 and 10 years. As mentioned above, adult AMN males are also at risk to develop cerebral ALD. Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%. The onset of cerebral-ALD is insidious. In boys it initially results in a decline of school performance. These early clinical symptoms are often misdiagnosed as attention deficit hyperactivity disorder which can delay the diagnosis of X-ALD. As the disease advances, overt neurologic deficits become apparent, which include auditory impairment, decreased visual acuity, spastic tetraparesis, cerebellar ataxia and seizures. At this stage progression is extremely rapid and devastating. Affected boys can lose the ability to understand language and walk within a few weeks. Eventually, patients are bedridden, blind, unable to speak or respond, requiring full-time nursing care and feeding by nasogastric tube or gastrostomy. Usually death occurs 2 to 4 years after onset of the initial symptoms, or – if well-cared for – patients may remain in this apparent vegetative state for several years. The rapid neurologic decline of patients with cerebral-ALD is associated with an inflammatory reaction in the cerebral white matter, which resembles but can be distinguished from what occurs in Multiple Sclerosis. The cerebral inflammatory reaction can be visualized using magnetic resonance imaging (MRI) after gadolinium administration, which delineates those areas in which there has been a breakdown of the blood-brain barrier.
- Women with X-ALD: As in many X-linked diseases, it was originally assumed that female carriers remain asymptomatic. However, in a recent study it was shown that more than 80% of women with X-ALD evidence AMN-like symptoms after the age of 60 years. The full text of this study can be viewed and downloaded (as a pdf). In general, the onset of neurologic symptoms occurs at a later age than in males with AMN; typically in the 4th to 5th decade of life. Motor disability and disease progression are generally less severe but some women with X-ALD are as severely impaired as male patients with X-ALD. It is important to note that AMN in women with X-ALD is often misdiagnosed as Multiple Sclerosis. Both adrenocortical failure and cerebral-ALD are very rare, ~2% and ~1%, respectively.
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.
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.
There is no general curative therapy for X-ALD.
- About 70% of male patients have adrenocortical insufficiency. For these patients, adrenal steroid replacement therapy is mandatory, and may be lifesaving, but it has no effect on neurological symptoms.
- For AMN, that affects 85% of all X-ALD patients (males and females combined), no curative therapy is available.
- Because VLCFA are toxic to myelin, the adrenals and testis, several attempts were made to lower the plasma concentrations of VLCFA. Dietary restriction of VLCFA intake alone has no effect on plasma VLCFA levels.
- VLCFA are primarily synthesized via chain elongation of shorter fatty acids. Addition of mono-unsaturated fatty acids to the culture medium of X-ALD fibroblasts reduced the VLCFA concentrations, probably by competitive inhibition of the endogenous elongation system of saturated fatty acids. This formed the basis of a dietary therapy. Oral administration of oleic acid in triglyceride form (GTO), and erucic acid in triglyceride form (GTE) normalized the plasma VLCFA levels within 1 month in most patients with X-ALD. The combination of GTO and GTE in a 4:1 ratio became known as “Lorenzo’s oil”, a tribute to Lorenzo Odone, the first patient treated with the mixture. Although Lorenzo’s oil was thought to hold great promise, several open-label trials have shown that the oil failed to improve neurological or endocrine function nor arrested the progression of the disease. (See the Lorenzo’s oil page for more details).
- 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 lovastatin as a VLCFA lowering therapy for X-ALD has been performed at the Academic Medical Center in Amsterdam. The results and conclusions that were published in the New England Journal of Medicine demonstrate that lovastatin treatment results in a small decrease in plasma VLCFA, but has no effect on VLCFA levels in red and white blood cells. (See the Lovastatin page for more details).
- In the search for compounds that may reduce VLCFA levels, bezafibrate, a drug used for the treatment of hyperlipidaemia, was identified as a VLCFA-lowering agent. Experiments in fibroblasts showed that bezafibrate reduced VLCFA levels by directly inhibiting the activity of the VLCFA-specific elongase ELOVL1. An open-label pilot study was performed to evaluate the effect of bezafibrate on VLCFA accumulation in blood cells of AMN patients. Unfortunately, bezafibrate failed to lower VLCFA levels in blood cells of X-ALD patients. Most likely this was attributable to its inability to reach adequate drug levels in patients.
- In boys and adolescents with early-stage cerebral involvement, allogeneic hematopoietic stem cell transplantation (HSCT) can arrest the progression of cerebral demyelination in X-ALD provided the procedure is performed at a very early stage of the disease. The efficacy of HSCT is based on the renewal of ALDP-deficient brain microglial cells by normal microglial cells that originate from the donor bone-marrow stem cells. (See the Hematopoietic stem cell transplantation (HSCT) and Cerebral ALD page for more details).
- Gene therapy: It is anticipated that in the not too distant future, transplantation of autologous hematopoietic cells that have been genetically corrected with a lentiviral vector prior to re-infusion might become an additional therapeutic option, based on the highly encouraging results reported in the first two treated patients (Cartier et al. 2009). (See the Gene Therapy for X-ALD for more details).