Facts on ALD

April 17th, 2017 |

Marc Engelen, M.D., Ph.D., Rachel Salzman, D.V.M. (CSO, The Stop ALD Foundation) and Stephan Kemp, Ph.D.

Definition

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.

Biochemistry

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 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 ALD 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. 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 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.

Epidemiology

ALD occurs all over the world and is observed across all ethnicities and geographies. The overall incidence of ALD is approximately 1 in 15.000 newborns.

Genetics

ALD is an X-linked disorder, which means that the ALD 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 ALD gene, there is no other X-chromosome for protection; therefore, he will experience ALD symptoms. Women have two X-chromosomes (XX; Figure 2). Women who carry the defective gene used to be referred to as “carriers” because it was thought that only a small percentage of these women would develop clinical symptoms. However, it is now clear that this is not the case (see below and the Women with ALD page). The clinical symptoms in women are somewhat milder than in men, however, 80% of women with ALD do eventually develop symptoms. Therefore, the terminology “ALD carriers” is misleading, and should no longer be used. The most likely explanation for women 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 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).

Figure 2: (Left) If a woman is a carrier for the defective ALD 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 ALD 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 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 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 ALD gene (he always passes his only (affected) X-chromosome on to his daughter).

Clinical course

Patients with ALD do not display any symptoms at birth. In males, the first manifestation of ALD is usually adrenal insufficiency, which can occur in young babies. In adulthood, males develop myelopathy (spinal cord disease). Males with ALD can develop progressive cerebral demyelination (cerebral ALD), both in childhood and adulthood. Cerebral ALD can either be the first manifestation of ALD or in addition to adrenal insufficiency and/or myelopathy (Figure 3). Women with ALD are also affected and not merely carriers of the ALD gene deficiency, as greater than 80% of these individuals develop the signs and symptoms associated with myelopathy by the age of 60 years. Women with ALD rarely develop adrenal insufficiency or cerebral demyelination.

 

Figure 3: The clinical spectrum of ALD in men. Patients with ALD 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 ALD gene and the storage of VLCFA in tissues results in adrenal insufficiency and myelopathy (together referred to as adrenomyeloneuropathy or AMN). Initiation of cerebral ALD is most likely defined by the interplay of the primary ALD 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 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. 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 ALD 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 ALD is rarely made during the first 3–5 years of clinical symptoms, unless other cases of ALD 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 AMN refers to male patients with both impaired adrenal function and a myelopathy.

Cerebral ALD: Boys and men with ALD 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 ALD 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 ALD. In adult patients the first symptoms are often psychiatric as well and can resemble depression or psychosis. In these patients, the diagnosis of ALD is often delayed; especially when no family history of ALD 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.

Women with ALD: As in many X-linked diseases, it was originally assumed that females carrying the deficient ALD gene remain asymptomatic. However, it is now established that this notion is incorrect. In fact, more than 80% of women with ALD develop symptoms by the age of 60 years (see also women with ALD). The full text of the research paper describing the sign and symptoms in women 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 women with ALD. It is important to note that the myelopathy in women with ALD is often misdiagnosed as multiple sclerosis. Both adrenal failure and cerebral ALD are very rare, less than 1%, respectively (see the Women with ALD page for more details).

Testing

ALD 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 women 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 women with ALD by genetic testing, and normal results can assure a woman that she is not a carrier of the defective ALD gene.

Newborn screening

Early diagnosis of ALD 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 ALD in newborns. In February 2016, ALD 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 ALD to their existing newborn screening program. Detailed and up-to-date information on ALD newborn screening can be found at the “newborn screening” page.

Research

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, 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?”.

Treatment

Today there is no curative treatment for ALD.

Adrenal steroid replacement therapy: Most male ALD patients develop adrenal insufficiency. Adrenal insufficiency of often the first manifestation of ALD: One insightful study revealed that 80% of neurologically pre-symptomatic boys with ALD 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 ALD 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 ALD 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 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. In fact, 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 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. (See the Lovastatin page for more details).

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 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.

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 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 (the patient’s own bone marrow cells) 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 (See the Gene Therapy for ALD for more details).

A 10 minute overview of ALD


Produced by Youreka Science in collaboration with ALD Connect, Inc.
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