Facts about ALD

Authors: 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 genetic disorder that affects the adrenal glands, spinal cord, and the white matter of the brain. It is severe and progressive. The disorder was first identified in 1923 and was formerly known as Schilder’s disease and sudanophilic leukodystrophy. In the 1970s, the name adrenoleukodystrophy was introduced to better describe its manifestations. The term ‘adreno’ refers to the adrenal glands, ‘leuko’ refers to the white matter of the brain, and ‘dystrophy’ means abnormal growth or development. It is important to note that this condition is distinct from ‘neonatal adrenoleukodystrophy,’ which is a disorder in the Zellweger spectrum of peroxisomal biogenesis disorders.

Biochemistry

ALD is a genetic metabolic storage disorder caused by a deficiency in a specific enzyme. This deficiency leads to the accumulation of harmful very long-chain fatty acids (VLCFA) in various tissues. The brain, spinal cord, testes, and adrenal glands are primarily affected. The accumulation of VLCFA damages the myelin sheath around nerves in the central nervous system, causing neurological problems. High levels of VLCFA negatively affect adrenal cells, contributing to Addison’s disease (adrenal insufficiency).

Figure 1: The excess VLCFA that accumulates in ALD is primarily due to the elongation of long-chain fatty acids. To maintain a healthy balance, cells must break down these excess VLCFA. This breakdown process takes place in peroxisomes. ALD is caused by gene mutations in ABCD1, which produces the ALD protein (ALDP). ALDP is responsible for transporting VLCFA into the peroxisomes. When ALDP is deficient, this transport is impaired, leading to an accumulation of VLCFA in cells, tissues and organs. The enzymes needed to break down VLCFA are present in peroxisomes. However, because of the transport blockage, the VLCFA cannot reach them.

Epidemiology

ALD is a global disease that affects people of all ethnicities and regions. It is estimated to affect approximately 1 in 15,000 newborns worldwide..

Genetics

ALD is a disorder caused by a defective gene called ABCD1 located on the X chromosome.
In males (XY), symptoms of ALD occur when the X chromosome carries the faulty gene. If a father carries the faulty gene, there isn’t an extra X chromosome for protection, resulting in symptoms.
Females (XX), who have two X chromosomes, have traditionally been called “carriers,” because it was assumed that only a small percentage would develop symptoms. However, this belief has changed. Although symptoms in females are typically less severe than in males, 80% of females with adrenoleukodystrophy will eventually develop symptoms. Therefore, the term “adrenoleukodystrophy carriers” is now considered misleading and it is recommended that it not be used. It is thought that the presence of a normal ABCD1 gene on an X chromosome explains the milder symptoms in females and protects them from the cerebral variant, which affects the brain.
Figure 2: Possible outcomes for each newborn: For affected females (left side of Figure 2): If an affected woman has a daughter, there is a 50% chance she will inherit the defective gene and a 50% chance she won’t be affected. If a son is born, there’s a 50% chance that he will have ALD, and a 50% chance that he will be unaffected.
For affected males (right side of Figure 2): Affected men pass their Y chromosome to all their sons, making them free of the disease. However, all daughters will inherit the defective X chromosome.

Clinical course

Individuals with ALD have no symptoms at birth. The clinical course is different in males and females.

In males

In males, the first noticeable symptom of ALD is often adrenal insufficiency, which can occur in infancy. Cerebral ALD, which is progressive cerebral demyelination, can develop in childhood or adulthood.
It may occur as the first sign of ALD or in association with adrenal insufficiency and/or myelopathy (see Figure 3). As men age, myelopathy, a spinal cord disease, becomes apparent.

Figure 3: This illustration shows the progression of ALD in males, highlighting ages at which different symptoms may begin. The blue bar represents adrenal insufficiency, which can begin as early as 5 months of age. The mauve bar represents myelopathy, a chronic spinal cord disease that develops in adulthood. The green bar represents cerebral ALD, which can occur at any age, with the youngest reported case being 3 years old. The ALD gene defect and storage of VLCFAs cause adrenal insufficiency and myelopathy, collectively known as adrenomyeloneuropathy. The onset of cerebral ALD is likely influenced by a combination of the primary gene defect, unknown environmental triggers, and/or genetic factors. Patients with adrenal insufficiency and/or myelopathy are at risk for developing cerebral ALD.

Adrenal insufficiency

Boys and men with ALD may experience adrenal insufficiency and potentially life-threatening Addisonian crises as their first symptoms, which can occur years or even decades before neurological symptoms develop. A study of boys who were pre-symptomatic for neurological symptoms found that 80% had adrenal insufficiency when they were diagnosed with ALD. Common signs of adrenal insufficiency include chronic fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, unexplained vomiting, nausea, diarrhea, low blood pressure (especially when standing, which can lead to dizziness or fainting), irritability, depression, cravings for salty foods, low blood sugar, headaches, and sweating.
Individuals may or may not have increased skin pigmentation due to excessive secretion of adrenocorticotropin hormone (ACTH).

Myelopathy

Most male patients with ALD who reach adulthood will eventually develop myelopathy. This typically occurs between the ages of 20 and 40. Symptoms primarily affect the spinal cord and peripheral nerves.
Characteristics:
Neurological disability is initially slowly progressive.
Diagnosis is rarely made during the first 3 to 5 years of symptoms unless other familial cases are identified.
Symptoms include slowly progressive gait disturbances due to leg stiffness and weakness.
Bladder dysfunction with urgency may develop, which may progress to complete incontinence.
Symptoms typically worsen over several years or decades, and most patients lose the ability to walk unassisted by their fifth or sixth decade.

Adrenomyeloneuropathy (AMN):

The term adrenomyeloneuropathy refers to male patients with both adrenal insufficiency and myelopathy.

Cerebral ALD

Boys and men with ALD may develop demyelinating lesions in the white matter of the brain, known as cerebral ALD. Recent observations suggest that the prevalence rates in adolescence and adulthood may be higher than previously thought, although onset has not been reported before the age of 3 years.
Historical perspective:
Traditionally, cerebral ALD was thought to be rare in adolescence (4-7%) and adulthood (2-5%). However, systematic MRI studies of a large group of males with ALD now suggest a potentially higher prevalence.
Risk factors and triggers:
Cerebral ALD is unpredictable in timing and onset. While head trauma has been reported as one of the possible triggers, other as yet unknown genetic and environmental factors are likely to play an important role.
Symptoms and progression:
Symptoms of cerebral ALD typically progress rapidly.
Males born with the disease have a 35 to 40% chance of developing cerebral ALD between the ages of 3 and 18.
Early symptoms of ALD in elementary school-aged boys include behavioral problems and learning disabilities. These symptoms are often misattributed to other disorders such as ADHD, which may delay the diagnosis of ALD.
In adults, initial symptoms may mimic depression or psychosis, which can also delay diagnosis, especially if in the absence of a family history or symptoms of adrenal insufficiency.
The progression of the disease is rapid at this stage, with patients losing their ability to understand speech and walk within months.
Eventually, patients become bedridden, blind, unable to speak or respond, and require full-time nursing care and tube feeding.
Patients with this disease usually die within 2 to 4 years of the onset of symptoms. However, with proper care, some patients can remain in a vegetative state for longer periods of time.

Women with ALD

It is now well established that more than 80% of women who carry the defective ALD gene will develop symptoms by the age of 60, contrary to the initial assumption that they will remain asymptomatic. Key points to consider.
Onset and progression:
Neurological symptoms in women typically begin at a later age (between 40 and 50 years) than in men with myelopathy.
Disease progression is generally slower than in males.
Distinctive feature:
Unlike males, fecal incontinence is a common complaint in females with ALD.
Risk of misdiagnosis:
Women with ALD often have their myelopathy misdiagnosed as multiple sclerosis
Adrenal insufficiency and cerebral ALD are rare:
Adrenal insufficiency and cerebral ALD are both very rare in women, occurring in less than 1% of cases each.
Research papers:
Two research papers describing the signs and symptoms in women with ALD are available for free download in (PDF) format.
Please see (Females with ALD) for more information.

Testing

Diagnosis of ALD involves a simple blood test that measures very long-chain fatty acid (VLCFA) levels, which is highly accurate in men of all ages. However, approximately 15% of women with ALD may have normal VLCFA levels, resulting in a “false negative” result.
VLCFA test accuracy:
The blood test for VLCFA is widely accepted and accurate in diagnosing males with ALD.
False negatives in women:
In approximately 15% of women with ALD, the VLCFA test may show normal levels, resulting in a “false negative” result.
DNA testing for women:
DNA testing is recommended for accurate identification of females with ALD, especially those with normal VLCFA levels.
Normal DNA test results reassure females that they are not carriers of the defective adrenoleukodystrophy gene.
C26:0-lysoPC as a diagnostic biomarker:
In 2020, C26:0-lysoPC levels were found to be elevated in all men and more than 99% of women with ALD [Jaspers et al 2020].
Even in women with ALD with normal VLCFA levels, C26:0-lysoPC levels were elevated in dried blood spots and plasma.
C26:0-lysoPC is considered a superior diagnostic biomarker for ALD compared to VLCFA analysis.

Newborn screening

Early diagnosis is critical to saving lives in ALD, and newborn screening plays a pivotal role in enabling prospective monitoring of adrenal function and the onset of cerebral ALD.
Key points include:
Newborn screening test:
A newborn screening test has been developed to detect elevated levels of VLCFA, specifically C26:0-lysoPC, in blood spots.
Introduction in New York:
On December 30, 2013, the State of New York began screening newborns for ALD.
United States Recommended Uniform Screening Panel (RUSP):
In February 2016, ALD was added to the United States Recommended Uniform Screening Panel (RUSP).
Global adoption:
Following the inclusion in the RUSP, other states and countries have initiated newborn screening programs or processes to add ALD to existing programs.
Taiwan initiated ALD newborn screening in January 2016.
The Netherlands began ALD newborn screening on October 1, 2023.
Regional pilots are underway in Italy, Israel, Japan and Spain.
Information resource:
Detailed and up-to-date information on ALD newborn screening can be found on the dedicated page titled Newborn screening”.

Treatment

There is currently no curative treatment for ALD. Various approaches have been explored to treat specific aspects of the disease:

Adrenal steroid replacement therapy
Adrenal insufficiency is common in ALD and is often the first manifestation.
Adrenal steroid replacement therapy is mandatory and can be life-saving, but it doesn’t affect neurological symptoms.

Treatment of Myelopathy
There is no curative therapy for myelopathy, which affects 85% of ALD patients (men and women combined).

Dietary restriction
Because very long-chain fatty acids (VLCFA) can be harmful to myelin, adrenal glands, and testes, various attempts have been made to reduce plasma concentrations of VLCFA. However, limiting VLCFA intake by dietary restriction alone does not affect plasma VLCFA levels.

Lorenzo’s oil
Lorenzo’s oil, a combination of oleic acid and erucic acid triglycerides, was thought to be promising.
However, clinical trials showed that it did not improve neurological or endocrine function or halt disease progression.
For more details, please visit the (Lorenzo’s oil) page.

Lovastatin
Lovastatin was initially considered as a VLCFA-lowering therapy, but conflicting results emerged.
Clinical trials showed a small reduction in plasma VLCFA but no effect at the cellular level.
For more information, please visit the (Lovastatin) page.

Bezafibrate
In the search for compounds that could potentially reduce VLCFA levels, bezafibrate, a drug commonly used to treat hyperlipidemia, 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. To evaluate the effect of bezafibrate on VLCFA accumulation in blood cells from ALD patients, an open-label pilot study was conducted. Unfortunately, the study showed that bezafibrate did not effectively reduce VLCFA levels in the blood cells of ALD patients. This lack of efficacy is likely due to the inability to achieve sufficient drug levels in patients.

Bone marrow transplant (HSCT)
In boys and adolescents with the early stages of cerebral ALD, allogeneic hematopoietic stem cell transplantation (HSCT) has the potential to halt the progression of cerebral demyelination. This positive outcome depends on the procedure being performed at a very early stage of the disease. The efficacy of HSCT is based on the replacement of ALDP-deficient brain microglial cells with normal microglial cells derived from donor bone marrow stem cells.
For more details, please visit the (Hematopoietic stem cell transplantation) page.

Gene therapy
Transplantation of autologous hematopoietic stem cells (the patient’s own bone marrow cells) genetically corrected ex vivo (outside the patient’s body) with a lentiviral vector prior to reinfusion is emerging as an additional therapeutic option. This optimism stems is based on the encouraging results reported in 2009 from the treatment of the first two ALD patients, as well as the more recent data from the Starbeam Study published in October 2017.
For more details, please visit the (Gene Therapy for ALD) page.

A 10 minute overview of adrenoleukodystrophy

Produced by Youreka Science in collaboration with ALD Connect, Inc.
Please see the ALD Connect Educational Videos & Webinars page for more videos.

Last modified | 2024-06-21