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.
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).
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.
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.
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).
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.
Adrenal insufficiency (or even a life threatening Addisonian crisis) can be the presenting symptom of ALD in boys and men, years or even decades before the onset of neurological symptoms. A study on neurologically pre-symptomatic boys with ALD showed that 80% of these boys already had impaired adrenal function at the time of diagnosis of ALD.
Cerebral ALD (childhood, adolescent and adult): Symptoms of cerebral ALD are in general rapidly progressive. A newborn male patient has a 35–40% risk to develop childhood cerebral ALD between the ages of 4 and 10 years, but never before the age of 3 years. Usually, affected boys initially have behavioral problems or learning deficits, often diagnosed as attention deficit disorder or hyperactivity, which can delay the diagnosis of 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. Cerebral ALD can also occur in adulthood. In adult patients the presentation and progression of cerebral ALD is similar, with behavioral changes and/or psychiatric symptoms. Adults who develop cerebral ALD often already have signs of AMN and adrenal insufficiency.
Adrenomyeloneuropathy (AMN): Virtually all male patients with ALD who reach adulthood develop AMN, typically between the 20-30 years of age. 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 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. All symptoms are progressive over decades. A retrospective study revealed that AMN patients have a high risk of developing the cerebral demyelinating form of the disease. The prognosis of these patients is as poor as in cerebral ALD patients. Approximately 70% of AMN patients have adrenal insufficiency and/or signs of testicular insufficiency. AMN patients frequently have scanty scalp hair that often develops during adolescence. AMN patients often show balding already in their twenties. Men with AMN can also develop cerebral ALD. The exact risk is not known and the initiation of cerebral ALD can not be predicted. The risk for developing cerebral ALD secondary to AMN is estimated to be at least 20% over a period of 10 years.
Women with 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 ALD develop 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 between 40 to 50 years of age. Motor disability and disease progression are generally less severe but some women with ALD are as severely impaired as male patients with ALD. It is important to note that AMN in women with ALD is often misdiagnosed as multiple sclerosis. Both adrenal failure and cerebral ALD are very rare, less than 1%, respectively.
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.
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.
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.
There is no general curative therapy for ALD.
Most male ALD patients develop adrenal insufficiency. Adrenal insufficiency of often the first manifestation of ALD: 80% of neurologically presymptomatic boys with ALD already had impaired adrenal function at the age of 4 years. 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 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 ALD fibroblasts reduces 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 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. Lorenzo’s oil was thought to hold great promise. However, several open-label trials have shown that the oil failed to improve neurological or endocrine function or that it could arrest 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 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 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 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 ALD, allogeneic hematopoietic stem cell transplantation (HSCT) can arrest the progression of cerebral demyelination in 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) 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 ALD for more details).