Facts on ALD
Authors: Marc Engelen, M.D., Ph.D., Rachel Salzman, D.V.M. (CSO, The Stop ALD Foundation), and Stephan Kemp, Ph.D.
Adrenoleukodystrophy (ALD) is a serious progressive, genetic disorder that affects the adrenal glands, the spinal cord, and the white matter (myelin) of the nervous system. It was first recognized in 1923 and has also been known as Schilder’s disease and sudanophilic leukodystrophy. In the 1970s, the name adrenoleukodystrophy was introduced as a means of better describing the disease manifestations. ‘Adreno’ refers to the adrenal glands; ‘leuko’ refers to the white matter of the brain, and ‘dystrophy’ means abnormal growth or development. This disorder has no relation to “neonatal adrenoleukodystrophy” which belongs to the peroxisomal biogenesis disorders of the Zellweger spectrum.
Adrenoleukodystrophy 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 to some cells and organs. For reasons that remain to be resolved, brain, spinal cord, testis and the adrenal glands are primarily affected. In the central nervous system, the build-up of VLCFA eventually destroys the myelin sheath that surrounds the nerves leading to neurologic problems. VLCFA are toxic to adrenal gland cells, and their malfunction causes Addison’s disease (adrenal insufficiency).
Figure 1: VLCFA that accumulate in adrenoleukodystrophy are mainly a result of long-chain fatty acid elongation. 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. Adrenoleukodystrophy is caused by mutations in the ABCD1 gene that produces the adrenoleukodystrophy 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 build-up of VLCFA in cells, tissues and organs. The enzymes that are required for the breakdown of VLCFA are present within the peroxisomes, but the VLCFA cannot reach them.
Adrenoleukodystrophy occurs all over the world and is observed across all ethnicities and geographies. The overall prevalence of adrenoleukodystrophy is approximately 1 in 15.000 newborns.
Adrenoleukodystrophy is an X-linked disorder, which means that the adrenoleukodystrophy gene (its official name is ABCD1) is located on the X-chromosome. Men have one X-chromosome and one Y-chromosome (XY; Figure 2). When the father is carrying the defective adrenoleukodystrophy gene, there is no other X-chromosome for protection; therefore, he will experience adrenoleukodystrophy symptoms. Females have two X-chromosomes (XX; Figure 2). Females who carry the defective gene used to be referred to as “carriers” because it was thought that only a small percentage of these females would develop clinical symptoms. However, it is now clear that this is not the case. See below and the page (Females with ALD). The clinical symptoms in females are somewhat milder than in men, however, 80% of females with ALD do eventually develop symptoms. Therefore, the terminology “adrenoleukodystrophy carriers” is misleading, and should no longer be used. The most likely explanation for females developing a milder form of the disease is the presence of a normal copy of the ABCD1 gene on their other X-chromosome. It is thought that the presence of cells that express the healthy copy of the ABCD1 gene protects females with ALD from developing the brain variant (cerebral ALD).
Figure 2: (Left) If a female is a carrier for the defective adrenoleukodystrophy gene she has the following possible outcomes with each newborn: when the child is a daughter, there is a 50% chance that the daughter receives the defective adrenoleukodystrophy gene 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 adrenoleukodystrophy and a 50% chance that he will be unaffected. (Right) For an X-linked disorder, such as adrenoleukodystrophy, if an affected man has children, then all of his sons will be free of the disease, since the father always passes his Y-chromosome on to his sons. However, all of his daughters will inherit the defective adrenoleukodystrophy gene (he always passes his only (affected) X-chromosome on to his daughter).
Patients with adrenoleukodystrophy do not display any symptoms at birth. In males, the first manifestation of adrenoleukodystrophy is usually adrenal insufficiency, which can occur in young babies. In adulthood, males develop myelopathy (spinal cord disease). Males with adrenoleukodystrophy can develop progressive cerebral demyelination (cerebral ALD), both in childhood and adulthood. Cerebral ALD can either be the first manifestation of adrenoleukodystrophy or in addition to adrenal insufficiency and/or myelopathy (Figure 3). Females with ALD are also affected and not merely carriers of the adrenoleukodystrophy gene deficiency, as greater than 80% of these individuals develop the signs and symptoms associated with myelopathy by the age of 60 years. Females with ALD rarely develop adrenal insufficiency or cerebral demyelination.
Figure 3: The clinical spectrum of adrenoleukodystrophy in men. Patients with adrenoleukodystrophy do not display any symptoms at birth. The colored bars indicate the age‐range of onset for adrenal insufficiency (blue bar), myelopathy (mauve bar) and cerebral ALD (green bar). Onset of adrenal insufficiency can be as early as 5 months of age. In adulthood, men invariably develop a chronic progressive myelopathy. Cerebral ALD can occur at any age, with the youngest reported patient at 3 years of age. The primary defect in the adrenoleukodystrophy gene and the storage of VLCFA in tissues results in adrenal insufficiency and myelopathy (together referred to as adrenomyeloneuropathy). Initiation of cerebral ALD is most likely defined by the interplay of the primary adrenoleukodystrophy gene defect and a combination of, as of yet unknown environmental triggers and/or genetic factors. It is important to recognize that patients with adrenal insufficiency and/or myelopathy remain at risk of developing cerebral ALD.
Adrenal insufficiency (or even a life threatening Addisonian crisis) can be the presenting symptom of adrenoleukodystrophy in boys and men, years or even decades before the onset of neurological symptoms. A study on neurologically pre-symptomatic boys with adrenoleukodystrophy showed that 80% of these boys already had impaired adrenal function at the time of diagnosis of adrenoleukodystrophy. The most common signs of adrenal insufficiency are chronic, or long lasting, fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain and unexplained vomiting. Other symptoms may include nausea, diarrhea, low blood pressure (that drops further when a person stands up, causing dizziness or fainting), irritability and depression, craving salty foods, low blood sugar, headache, or sweating. Individuals may or may not have increased skin pigmentation resulting from excessive adrenocorticotropin hormone (ACTH) secretion.
Myelopathy: Virtually all male patients with adrenoleukodystrophy who reach adulthood develop a myelopathy, typically between the 20-40 years of age. Symptoms are limited to the spinal cord and the peripheral nerves. Initially, the neurologic disability is slowly progressive. The diagnosis of adrenoleukodystrophy is rarely made during the first 3–5 years of clinical symptoms, unless other cases of adrenoleukodystrophy have been identified in the same family. Patients develop a slowly progressive gait disorder due to stiffness and weakness of the legs. Individuals can also develop bladder dysfunction with urinary urgency, which can progress to full incontinence. All symptoms are progressive over years or decades, with most patients losing unassisted ambulation by the 5th – 6th decade of life.
Adrenomyeloneuropathy (AMN): The term adrenomyeloneuropathy refers to male patients with both impaired adrenal function and a myelopathy.
Cerebral ALD: Boys and men with adrenoleukodystrophy are at risk of developing demyelinating lesions in the cerebral white matter (cerebral ALD). The onset of cerebral ALD has never been reported before the age of 3 years. In the past, cerebral ALD was considered to be rare in adolescence (4‐7%) and adulthood (2‐5%). However, now that we systematically follow a large group of men with adrenoleukodystrophy with yearly MRI scans it appears that these numbers are higher. Currently, we cannot predict if or when a patient will develop cerebral ALD. A possible environmental trigger is head trauma, but other – as of yet – unknown genetic and environmental factors are likely required for the development of cerebral ALD. Symptoms of cerebral ALD are in general rapidly progressive. A newborn male patient has a 35–40% risk to develop cerebral ALD between the ages of 3 and 18 years. In elementary school-aged boys, the first symptoms are usually behavioral problems and learning deficits manifesting as a decline in school performance. These early clinical symptoms are often initially attributed to other disorders such as attention deficit/hyperactivity disorder, which can delay the diagnosis of adrenoleukodystrophy. In adult patients the first symptoms are often psychiatric as well and can resemble depression or psychosis. In these patients, the diagnosis of adrenoleukodystrophy is often delayed; especially when no family history of adrenoleukodystrophy is present and when clinical symptoms of adrenal insufficiency are absent. As the disease progresses, overt neurologic deficits become apparent, which include hearing and visual impairment, weakness of the arms and legs, problems with coordination and seizures. At this stage progression is extremely rapid and wholly devastating. Affected patients can lose the ability to understand language and walk within a few months. Eventually, patients are bedridden, blind, unable to speak or respond, requiring full-time nursing care and feeding by nasogastric tube or gastrostomy. Death generally 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 years.
Females with ALD: As in many X-linked diseases, it was originally assumed that females carrying the deficient adrenoleukodystrophy gene remain asymptomatic. However, it is now established that this notion is incorrect. In fact, more than 80% of females with ALD develop symptoms by the age of 60 years. The full text of the research paper describing the sign and symptoms in females with ALD can be viewed and downloaded (as a pdf). In general, their onset of neurologic symptoms occurs at a later age than in males with myelopathy; typically, between 40 to 50 years of age. Disease progression is generally slower than in males. Interestingly, and in contrast to males, fecal incontinence is a frequent complaint in females with ALD. It is important to note that the myelopathy in females with ALD is often misdiagnosed as multiple sclerosis. Both adrenal failure and cerebral ALD are very rare, less than 1%, respectively. For more details see (Females with ALD).
Adrenoleukodystrophy is diagnosed by a simple blood test, which measures the very long-chain fatty acids levels. This test is accurate in males, and is widely accepted as a highly accurate means of diagnosing males of all ages. However, in about 20% of females with ALD the VLCFA test shows normal levels and thus provides the individual with a “false negative” result. One way to accurately identify “false negative” patients is via a DNA test. This laboratory test permits accurate identification of females with ALD by genetic testing, and normal results can assure a female that she is not a carrier of the defective adrenoleukodystrophy gene.
Early diagnosis of adrenoleukodystrophy is the key to saving lives, because newborn screening allows prospective monitoring for adrenal function and the onset of cerebral ALD. A newborn screening test has been developed. It detects elevated VLCFA levels (as C26:0-lysoPC) in bloodspots. On December 30, 2013, the state of New York initiated screening for adrenoleukodystrophy in newborns. In February 2016, adrenoleukodystrophy was added to the United States Recommended Uniform Screening Panel (RUSP). Since then other states and countries have started newborn screening programs, or have initiated processes intended to add adrenoleukodystrophy to their existing newborn screening program. Detailed and up-to-date information on adrenoleukodystrophy newborn screening can be found at the page “Newborn screening”.
Extensive research on adrenoleukodystrophy is being done around the world. In 1993, the gene for adrenoleukodystrophy 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, such as: “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 a myelopathy at a later age?”.
Today there is no curative treatment for adrenoleukodystrophy.
Adrenal steroid replacement therapy: Most male adrenoleukodystrophy patients develop adrenal insufficiency. Adrenal insufficiency of often the first manifestation of adrenoleukodystrophy: One insightful study revealed that 80% of neurologically pre-symptomatic boys with adrenoleukodystrophy who were identified through extended family screening already had impaired adrenal function at the age of 4 years. For these patients, adrenal steroid replacement therapy is mandatory, and may be lifesaving, however, successfully managing adrenal dysfunction has no effect on neurological symptoms.
For the myelopathy, that affects 85% of all adrenoleukodystrophy patients (males and females combined), no curative therapy is available.
Dietary restriction: 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.
Lorenzo’s oil: VLCFA are primarily synthesized via chain-elongation of shorter fatty acids. In the laboratory, the addition of mono-unsaturated fatty acids to the cell culture medium of adrenoleukodystrophy fibroblasts reduces the VLCFA concentrations to normal levels. This can be explained because the enzymes that are required for the synthesis of VLCFA are the same for mono-unsaturated fatty acids and for saturated fatty acids. But their affinity for the monounsaturated fatty acids is higher. This finding formed the basis of a dietary approach. 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 adrenoleukodystrophy. 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. More details at the page (Lorenzo’s oil).
Lovastatin was demonstrated to have an effect on VLCFA. This finding, however, could not be reproduced by others. In fact, later experiments showed that statins had no effect on brain and adrenal VLCFA levels in adrenoleukodystrophy 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 adrenoleukodystrophy has been performed at the Academic Medical Center in Amsterdam. The results and conclusions demonstrate that lovastatin treatment results in a small decrease in plasma VLCFA, but it does not affect VLCFA at the cellular level, since C26:0 levels in red and white blood cells were unchanged. More details at the page (Lovastatin).
Bezafibrate: 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 adrenoleukodystrophy patients. Unfortunately, bezafibrate failed to lower VLCFA levels in blood cells of adrenoleukodystrophy patients. Most likely this was attributable to its inability to reach adequate drug levels in patients.
Bone-marrow transplant: In boys and adolescents with early-stage cerebral ALD, allogeneic hematopoietic stem cell transplantation (HSCT) can arrest the progression of cerebral demyelination in adrenoleukodystrophy 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. More details at the page (Hematopoietic stem cell transplantation).
Gene therapy: It is anticipated that in the not too distant future transplantation of autologous (the patient’s own bone marrow cells) hematopoietic stem cells that have been genetically corrected ex vivo (outside of the patient’s body) with a lentiviral vector prior to re-infusion might become an additional therapeutic option. This optimism is based on the highly encouraging results reported in 2009 in the first two treated ALD patients, and on the recent data from the Starbeam Study published in October 2017. More details at the page (Gene Therapy for ALD).
A 10 minute overview of adrenoleukodystrophy
Produced by Youreka Science in collaboration with ALD Connect, Inc.
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Last modified | 2019-07-12