Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is a rare X-linked genetic disorder that primarily affects the brain and adrenal glands, leading to a range of symptoms from adrenal insufficiency to progressive neurological decline. It is caused by mutations in the ABCD1 gene, resulting in the accumulation of very long chain fatty acids (VLCFA) in the body, which can severely impact cellular metabolism. The disease manifests differently in males and females, with males experiencing more severe symptoms, including cognitive disturbances, seizures, and vision loss, while females often have milder and slower-progressing symptoms. There are three main forms of ALD: childhood cerebral, adult-onset adrenomyeloneuropathy, and cases where adrenal insufficiency is the only symptom.
Treatment options include steroid hormone replacement for adrenal insufficiency, supportive care for neurological symptoms, and, in some cases, bone marrow transplantation, which is considered a potential cure when performed early. Dietary interventions and gene therapy are also being explored, with recent advances showing promise in using a patient’s own stem cells to replace the defective gene. Research continues into effective treatments and management strategies for this complex condition, which affects approximately 1 in 20,000 male births.
Adrenoleukodystrophy
ALSO KNOWN AS: Melanodermic leukodystrophy, Siemerling-Creutzfeldt disease, X-linked ALD
ANATOMY OR SYSTEM AFFECTED: Brain, ears, endocrine system, eyes, genitals, glands, nervous system, psychic-emotional system, reproductive system, respiratory system, skin
DEFINITION: A variable X-linked genetic disorder with symptoms ranging from adrenal insufficiency to progressive neurological deterioration.
CAUSES: Mutations in the ABCD1 gene, inherited in more than 90 percent of cases
SYMPTOMS: Adrenal insufficiency, increased skin pigment, hyperactivity, difficulty swallowing, difficulty talking, seizures, small testes, psychosis, vision loss, hearing loss, paresis (weakness)
DURATION: Lifelong
TREATMENTS: Oral steroids, bone marrow transplants
Causes and Symptoms
X-linked adrenoleukodystrophy (ALD) is caused by mutations in the ABCD1 gene. The ABCD1 gene codes for the ALD protein. This protein is located in the membrane of an essential cellular organelle, the peroxisome, which has a role in cellular metabolism. Very long chain fatty acids (VLCFA) are metabolized in the peroxisome. The buildup of saturated VLCFA in tissues causes the symptoms of X-linked adrenoleukodystrophy. A diagnosis can be made in males by identifying an elevated VLCFA level in body fluids. In females, VLCFA levels are not reliable, and genetic testing is necessary.
The symptoms of X-linked ALD vary from one individual to the next, even within the same family. The gene mutation or level of VLCFA in body fluids is not a predictor of symptom type or age of onset. Because the ABCD1 gene is located on the X chromosome, the disease presentation is different in males and females. The clinical presentation of X-linked ALD in males can be categorized into three groups. About 35 to 50 percent of males with X-linked ALD have a childhood cerebral disorder. The age of onset varies from three to ten years but can occur as late as twenty-one years of age. Boys with the cerebral type of X-linked ALD have a progressive loss of the myelin that encloses the nerves in the brain (demyelination). As the condition progresses, characteristic abnormalities can be seen on brain magnetic resonance imaging (MRI). The neurological symptoms may include cognitive disturbances, hyperactivity, seizures, and psychosis. Boys with X-linked ALD may also experience vision and hearing loss. They enter a vegetative state and die within approximately two to four years of the onset of neurological symptoms. Insufficient hormone production from the adrenal gland, also known as Addison’s disease, is identified in 90 percent of boys with the childhood cerebral type of X-linked ALD. The symptoms of untreated may include vomiting, fatigue, low blood pressure, weakness, increased skin pigmentation, and coma. Adrenal insufficiency can be detected through identification of an elevated plasma adrenocorticotropin (ACTH).
The second type of X-linked ALD is an adult-onset disorder typically referred to as adrenomyeloneuropathy (AMN). The symptoms of AMN include progressive weakness of the legs, paresis, sphincter disturbance, and sexual dysfunction. Onset of symptoms ranges from the second to fourth decade but typically occurs in the late twenties. About 70 percent of men with AMN also have Addison’s disease.
For approximately 10 percent of males with X-linked ALD, Addison’s disease is the only symptom, which usually manifests initially at around age eight but can start in adulthood. Most men with Addison’s disease as the only symptom of X-linked ALD will eventually develop neurological involvement. Rarely, males with an ABCD1 gene mutation are asymptomatic.
Approximately 10 to 50 percent of females with an ABCD1 gene mutation will have neurological symptoms, which are milder and progress more slowly than in men but are otherwise similar to AMN. The onset of symptoms is typically in a person’s thirties.
Treatment and Therapy
The treatment for the adrenal insufficiency identified in most males with X-linked ALD is steroid hormone replacement.
For the childhood cerebral type, management is typically supportive, and stimulants can be helpful for treatment of hyperactivity. However, bone marrow transplantation is a permanent cure. Because it is associated with a high mortality rate of about 20 percent, as of 2009, it is only recommended in the early stages of cerebral involvement, when abnormalities are first noted on brain MRI.
For males with AMN and symptomatic females, treatment is typically supportive, including physical therapy and psychological counseling.
Perspective and Prospects
The first description of symptoms consistent with childhood cerebral X-linked adrenoleukodystrophy in the medical literature was by Ernst Siemerling and Hans Gerhard Creutzfeldt in 1923. The first adult patient with AMN was described by Herbert Budka in 1976. The incidence of X-linked ALD is now estimated at 1 in 20,000 male births.
The first attempt to cure X-linked ALD was in the 1980s. The proposed treatment was dietary restriction of VLCFA; however, the levels of VLCFA were not lowered in body fluids. The next attempt was a combination of dietary restriction and administration of a dietary supplement called “Lorenzo’s oil,” a mixture of glyceryl trioleate and glyceryl trierucate. This combination lowers the level of VLCFA in the body fluids. Unfortunately, in symptomatic patients, it does not alter the course of their disease. In presymptomatic patients, some studies have suggested that administration of Lorenzo’s oil and dietary restriction of VLCFA reduces the chances of cerebral or neurological involvement. The efficacy of Lorenzo’s oil is an area of research. Gene therapy has also been an area of research for the treatment of X-linked ALD. The US Food & Drug Association (FDA) approved a gene therapy in 2022 for boys with ALD who have few or no symptoms. It uses a boy's own stem cells, taken from his blood. The cells are then treated in a lab and then used to replace the defective or missing ABCD1 gene. A clinical trial in boys ages four to seventeen found that 90 percent of boys treated with this type of gene therapy were alive two years later and free of symptoms. Researchers believe the benefit will last at least as long as ten years.
Bibliography
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Wanders, Ronald, J.A. and Marc Engelen. "Clinical Features, Evaluations, and Diagnosis of X-Linked Adrenoleukodystrophy. Up To Date, 19 Mar. 2024, ww.uptodate.com/contents/clinical-features-evaluation-and-diagnosis-of-x-linked-adrenoleukodystrophy. Accessed 27 Mar. 2024.
Williams, Emily. "Matthew, the 'Wee Marvel': One of the First ALD Gene Therapy Recipients." Boston Children's Hospital, 22 Sept. 2022, answers.childrenshospital.org/first-gene-therapy-ald-recipient/. Accessed 27 Mar. 2024.