Adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the brain, spinal cord, and adrenal glands. It disrupts the breakdown of very long-chain fatty acids (VLCFAs) in the body, leading to their accumulation in tissues, particularly in the nervous system and adrenal cortex.

The name describes a condition of abnormal development affecting the brain’s white matter and the adrenal glands. The white matter is primarily composed of nerve fibers covered in myelin, a fatty substance that acts as an insulator. The myelin sheath is essential for fast and efficient transmission of nerve signals. In ALD, this myelin is progressively destroyed, a process called demyelination, which short-circuits the brain’s ability to communicate with the rest of the body.

The core biochemical problem in ALD is the body’s inability to break down a specific type of fat called very long-chain fatty acids (VLCFAs).

To understand this, it is helpful to use an analogy. Think of your cells as tiny factories, and VLCFAs are a type of industrial waste product that these factories produce. Each factory has a specialized recycling center called a peroxisome, which is equipped with the machinery (enzymes) needed to break down this fatty waste. In ALD, a critical piece of that machinery, a transporter protein that brings the VLCFAs into the recycling center, is broken. As a result, the fatty waste cannot be processed and begins to accumulate to toxic levels inside the cells. This buildup is particularly damaging to the myelin in the brain and spinal cord and to the cells of the adrenal cortex, causing them to malfunction and die.

In my experience, ALD is often first detected when a child presents with unexplained behavioral or learning changes, and early intervention can make a major difference in progression.

ALD is caused by mutations in the ABCD1 gene. This gene, which is located on the X chromosome, contains the complete set of instructions for making a protein called the Adrenoleukodystrophy Protein (ALDP).

The ALDP is the transporter protein that sits on the peroxisome surface. Its specific task is to transport VLCFAs into the peroxisome so they can be broken down. When the ABCD1 gene is mutated, the ALDP is either not produced at all or is misshapen and cannot function correctly. Without a working transporter, VLCFAs accumulate in the body’s cells and tissues, leading to the destructive inflammatory and demyelinating processes that characterize the disease.

Clinically, I emphasize that while the genetic mutation is fixed at birth, symptoms may not appear until months or years later, which makes early screening vital.

Adrenoleukodystrophy is an X-linked recessive genetic disorder. This specific pattern of inheritance explains why the disease affects males much more severely and frequently than females.

• Males have one X chromosome and one Y chromosome (XY). If their single X chromosome carries the mutated ABCD1 gene, they will develop the disease.
• Females have two X chromosomes (XX). If one of their X chromosomes has the mutated gene, they are considered “carriers.” Their other, healthy X chromosome can usually produce enough of the normal ALDP to compensate, so they typically do not develop the severe cerebral form of the disease.

The inheritance pattern for a female carrier is as follows for each pregnancy:

• There is a 25% chance of having an affected son (who inherits her mutated X chromosome).
• There is a 25% chance of having an unaffected son (who inherits her normal X chromosome).
• There is a 25% chance of having a carrier daughter (who inherits her mutated X chromosome).
• There is a 25% chance of having a non-carrier daughter (who inherits her normal X chromosome).

An affected father cannot pass the disease to his sons (because he gives them his Y chromosome), but he will pass the mutated gene to all of his daughters, making them carriers. While most cases are inherited, the condition can also arise from a new, spontaneous mutation in a family with no prior history of the disease.

Parents often ask if anything could’ve been done to prevent it, and I reassure them it’s a genetic issue present from conception, not related to pregnancy, diet, or exposure.

ALD is a single disease caused by one faulty gene, but it has a number of different clinical presentations, known as phenotypes. The reasons for this wide variability are not yet fully understood.

The main phenotypes of ALD include:

• Childhood Cerebral ALD (cALD): This is the most common and by far the most devastating form, affecting about 35-40% of boys with the genetic mutation. These boys are typically healthy and develop normally for the first few years of life. Then, usually between the ages of 4 and 10, they begin to show neurological symptoms that progress with terrifying speed. Initial symptoms can be subtle and mistaken for behavioral problems, but they are followed by rapid neurological decline. Symptoms include:
  • Behavioral changes, such as withdrawal, aggression, or difficulty concentrating in school.
  • Vision problems, including difficulty reading or crossed eyes.
  • Hearing loss.
  • Loss of coordination and balance.
  • Difficulty with speech and swallowing.
  • Seizures.
  • If left untreated, cALD progresses relentlessly, leading to a vegetative state and death within a few years.
• Adrenomyeloneuropathy (AMN): This is the most common form in adults, typically appearing in a person’s 20s or 30s. It is a more slowly progressive disorder that primarily affects the spinal cord. Symptoms include:
  • Progressive stiffness, weakness, and pain in the legs (spastic paraparesis).
  • Bladder and bowel control problems.
  • Sexual dysfunction.
  • Adrenal insufficiency.
  • Many men with AMN will eventually develop cerebral involvement later in life.
• “Addison’s Only” Presentation: Some individuals with the ABCD1 mutation will present only with adrenal insufficiency (Addison’s disease), where the adrenal glands fail to produce enough cortisol. This can occur in childhood or adulthood. These individuals remain at risk for developing AMN or cerebral ALD later.
• Female Carriers: While once thought to be asymptomatic, it is now known that a significant percentage of female carriers (up to 50% or more) will develop some neurological symptoms later in life, usually after age 40. These symptoms typically resemble a milder form of AMN, with progressive leg stiffness and sensory changes.

Clinically, I’ve seen ALD begin subtly, like minor attention issues, before progressing to severe neurologic impairment. That’s why early screening and vigilant follow-up are so critical.

Early diagnosis is key, especially in boys with a family history or early signs of adrenal insufficiency or learning difficulties.

• Newborn Screening: The most important tool for diagnosing ALD is newborn screening. A simple blood spot test, taken from a heel prick in the first days of life, can measure the level of very long-chain fatty acids. An elevated VLCFA level is a clear indicator of ALD. This allows doctors to identify affected boys at birth, monitor them closely, and intervene with potentially life-saving treatment at the earliest possible moment.
• Diagnostic Confirmation: If newborn screening is positive or if ALD is suspected based on symptoms, the diagnosis is confirmed with:
  • A VLCFA blood test.
  • Genetic testing to identify ABCD1 gene mutations.
• Monitoring: Once diagnosed, an individual will have regular brain MRIs to look for the first signs of cerebral demyelination and regular blood tests (like the ACTH stimulation test) to monitor for adrenal insufficiency.

In my practice, identifying ALD before symptoms start is ideal. It opens the door to early interventions that can halt or delay progression.

Treatment varies by stage and type of ALD. While there is no cure, some therapies can slow disease progression, manage symptoms, and support adrenal function.

1. Hematopoietic Stem Cell Transplant (HSCT)

For boys with early-stage cerebral ALD, a hematopoietic stem cell transplant (also known as a bone marrow transplant) is the only treatment currently available that can halt the progression of the demyelination in the brain.

• The Window of Opportunity: A transplant is only effective if performed when there are early changes on the brain MRI but before significant neurological symptoms have begun.
• The Procedure: The transplant involves using high-dose chemotherapy to destroy the patient’s own faulty bone marrow, which is then replaced with healthy, blood-forming stem cells from a matched donor. The new donor cells produce healthy immune cells that can travel to the brain and provide the functional enzyme needed to break down VLCFAs, stopping the inflammatory process.
• Risks: HSCT is a very high-risk procedure with significant potential complications, including graft-versus-host disease and infection.

2. Gene Therapy

This is a groundbreaking new therapeutic option for early cALD.

• The Procedure: In gene therapy, the patient’s own stem cells are removed from their body. In the laboratory, a corrected copy of the ABCD1 gene is inserted into these cells using a modified, safe virus. These genetically corrected stem cells are then infused back into the patient.
• Benefits: Because it uses the patient’s own cells, gene therapy eliminates the risk of graft-versus-host disease and the need to find a matched donor. Early results have been very promising (as described by sources like the Kennedy Krieger Institute).

3. Adrenal Hormone Replacement

All males diagnosed with ALD must be regularly monitored for adrenal insufficiency. If the adrenal glands begin to fail, they must be treated with lifelong steroid hormone replacement therapy. This is a simple and life-saving intervention.

4. Lorenzo’s Oil

This is a dietary oil made famous by the 1992 film of the same name. It is a mixture of oleic acid and erucic acid. While it can lower the level of VLCFAs in the blood, clinical trials have shown that it does not stop the progression of the disease or improve symptoms in boys who already have cerebral ALD. Some evidence suggests it may help to delay the onset of symptoms in boys who are diagnosed presymptomatically, but its role remains under study (NINDS, 2023).

I always advise families that early transplant or gene therapy is the best hope for preserving brain function, but timing is everything.

Adrenoleukodystrophy is a devastating genetic disorder, with its childhood cerebral form representing one of the most rapidly progressive and cruel diseases in pediatric neurology. The stark contrast between a healthy young boy and one in the grips of this disease underscores the urgency of early intervention. The entire prognosis for cerebral ALD hinges on one critical factor: pre-symptomatic diagnosis through newborn screening. Identifying affected boys at birth provides the narrow window of opportunity needed to proceed with a potentially life-saving stem cell transplant or gene therapy before the brain is irreversibly damaged. For patients and their families, the journey with ALD is one of constant vigilance and proactive care.

National Institute of Neurological Disorders and Stroke (NINDS). (2023). Adrenoleukodystrophy. Retrieved from https://www.ninds.nih.gov/health-information/disorders/adrenoleukodystrophy

National Organization for Rare Disorders (NORD). (2021). Adrenoleukodystrophy. Retrieved from https://rarediseases.org/rare-diseases/adrenoleukodystrophy/

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2021). X-linked adrenoleukodystrophy. Retrieved from https://rarediseases.info.nih.gov/diseases/5782/x-linked-adrenoleukodystrophy