Adrenoleukodystrophy (ALD) is a genetic disorder that prevents the body from breaking down certain fats, leading to damage in the brain, spinal cord, and adrenal glands. It affects roughly 1 in 20,000 to 50,000 people worldwide and is the most common genetic disorder involving peroxisomes, the tiny cellular structures responsible for processing fats. Because the gene responsible sits on the X chromosome, ALD primarily causes severe disease in boys and men, though the majority of female carriers eventually develop symptoms too.
How ALD Damages the Nervous System
ALD is caused by a mutation in a single gene called ABCD1. This gene provides instructions for a transporter protein that moves very long-chain fatty acids (VLCFAs) into peroxisomes, where they would normally be broken down. When the transporter doesn’t work, these oversized fat molecules accumulate in tissues throughout the body, particularly in the protective myelin coating around nerve fibers, the adrenal glands, and the testes.
Myelin normally contains fatty acids with chain lengths of 16 to 20 carbons. In ALD, the brain’s white matter becomes loaded with fatty acids 22 carbons or longer. These abnormally long molecules destabilize myelin’s structure, triggering a chain reaction: the cells that produce myelin die off, immune cells flood in carrying myelin debris, and inflammation escalates. The result is progressive demyelination, where the insulating layer around nerves breaks down, disrupting the brain’s ability to send signals.
Types of ALD and How They Differ
All forms of ALD stem from the same gene mutation, but the disease shows up in dramatically different ways depending on when and where it strikes. The same family can have members with very different forms, and researchers still don’t fully understand what determines which type a person develops.
Childhood Cerebral ALD
This is the most severe form. Risk is highest between ages 3 and 12, with a median age of diagnosis around 7. The earliest known case showed brain changes on MRI at 19 months, though visible neurological signs before age 3 are rare. In about 80% of cases, damage begins at the back of the brain in the parieto-occipital white matter, while 15 to 17% start with frontal involvement.
Early symptoms are deceptively ordinary. Boys often first show what looks like ADHD, anxiety, or behavioral problems. Teachers may notice trouble with spatial orientation, hand-eye coordination, or keeping up academically. Increased irritability, agitation, sleep disturbance, reduced eye contact, and less spontaneous speech can all precede the more obvious neurological decline. Once the inflammatory process accelerates, deterioration can be rapid, particularly in younger children. A small subset of patients do experience spontaneous arrest of the disease after an initial period of worsening, but this is uncommon.
Adrenomyeloneuropathy (AMN)
AMN is the most common form in adults, typically emerging in a man’s 20s or 30s. Rather than explosive brain inflammation, AMN involves slow, progressive damage to the spinal cord and peripheral nerves. Symptoms include stiffness and weakness in the legs, bladder and bowel control problems, and nerve pain. Over time, many men with AMN need a cane, walker, or wheelchair. Cognitive function generally remains intact in AMN, distinguishing it from the childhood cerebral form.
Adrenal Insufficiency Alone
Some males with ALD develop problems only with their adrenal glands, at least initially. The adrenal glands stop producing enough cortisol and sometimes aldosterone, hormones essential for managing stress, blood pressure, and electrolyte balance. About 70% of males with ALD or AMN develop adrenal insufficiency, and adrenal function is abnormal in 90% of boys who already have neurological symptoms. In some cases, adrenal problems appear years before any neurological signs, making ALD an important consideration when a boy or young man is diagnosed with unexplained adrenal failure.
Female Carriers Are Not Spared
For decades, women who carried the ALD gene mutation were told they would likely remain unaffected. That understanding has changed substantially. Up to 80% of female carriers develop symptoms of spinal cord and nerve involvement during their lifetime. Gait problems affect about 65%, bladder and bowel dysfunction over 79%, sensory complaints around 81%, and neuropathic pain over 80% of symptomatic women. Restless leg syndrome occurs in nearly half. These symptoms resemble AMN and tend to appear later in life than they do in men, but they can significantly affect quality of life. About 5% of female carriers also develop adrenal insufficiency.
How ALD Is Diagnosed
The standard first step is a blood test measuring VLCFA levels. Elevated levels of specific fatty acids, particularly those with 26-carbon chains, are a hallmark of the disease. This test is sensitive but not perfectly specific, so genetic testing to confirm the ABCD1 mutation is needed to lock in the diagnosis.
For boys and men with suspected brain involvement, MRI is essential. Doctors use a standardized scoring system called the Loes score to quantify how much white matter damage exists. The scale runs from 0 to 34, with higher scores indicating more extensive disease. It divides the brain’s white matter into specific territories and grades each for the extent of abnormality and whether involvement is one-sided or bilateral. The score also accounts for brain shrinkage. This number plays a critical role in treatment decisions, particularly in determining whether a child qualifies for a stem cell transplant.
ALD was added to the U.S. Recommended Uniform Screening Panel for newborns, and screening programs have expanded across multiple states. Newborn screening uses dried blood spots to measure a specific marker (a form of the accumulated fatty acid). Early detection through newborn screening is important because the most effective treatments work only when started before significant brain damage has occurred.
Stem Cell Transplant for Cerebral ALD
For boys with early cerebral ALD, a transplant of blood-forming stem cells from a matched donor is currently the most established treatment. The transplanted cells produce functional versions of the missing transporter protein, and over time, donor-derived immune cells in the brain can help stabilize or halt the inflammatory process. The procedure carries significant risks, including graft-versus-host disease and complications from the intensive chemotherapy required beforehand. Timing is critical: transplants performed when brain involvement is still minimal (low Loes scores) have far better outcomes than those done after substantial damage has already occurred. This is why newborn screening and regular MRI monitoring of at-risk boys are so important.
Gene Therapy: Promise and Serious Risks
A gene therapy called Skysona (elivaldogene autotemcel) received accelerated FDA approval in September 2022 for boys ages 4 to 17 with early, active cerebral ALD. It works by collecting a patient’s own blood-forming stem cells, inserting a functional copy of the ABCD1 gene using a modified virus, and infusing the corrected cells back. This avoids the need for a matched donor and eliminates the risk of graft-versus-host disease.
However, Skysona carries a serious safety concern. At the time of approval, blood cancers (myelodysplastic syndrome) had been reported in about 4% of clinical trial participants. As of July 2025, that number has more than tripled to 15%, with 10 out of 67 trial participants developing blood cancers including myelodysplastic syndrome and acute myeloid leukemia. One death related to treatment for the malignancy has occurred. These cancers appeared anywhere from 14 months to 10 years after treatment. Because of this risk, the FDA now restricts Skysona to patients who do not have a suitable matched donor available for a traditional stem cell transplant. Anyone who receives the therapy requires lifelong monitoring, including blood counts at least every three months.
Managing Adrenal Insufficiency
Because adrenal insufficiency affects the large majority of males with ALD, hormonal monitoring begins early. Current guidelines recommend screening adrenal function starting at 6 months of age in boys known to carry the mutation, with testing every 3 to 6 months until age 10, then yearly from puberty onward.
When adrenal insufficiency is confirmed, treatment involves daily replacement of the hormones the adrenal glands can no longer produce. Children typically take hydrocortisone, while adults may use hydrocortisone or cortisone acetate. A small number of patients also need a mineralocorticoid to help regulate salt and fluid balance. In infants, an oral sodium supplement is sometimes added. Treatment effectiveness is tracked through regular checks of growth, weight, blood pressure, and energy levels in children, and yearly evaluations in adults. Adequate adrenal hormone replacement is essential because an adrenal crisis triggered by illness or stress can be life-threatening.
Lorenzo’s Oil
Lorenzo’s oil, a mixture of two specific fats, was developed in the 1980s by the parents of a boy with ALD and became widely known through a 1992 film. The oil works by reducing levels of the accumulated fatty acids in the blood. In boys who are asymptomatic and have normal brain MRIs, a carefully supervised regimen of Lorenzo’s oil is associated with a roughly twofold reduction in the risk of developing brain MRI abnormalities. For patients who already have neurological symptoms, however, multiple clinical trials reached a consensus that the oil does not significantly alter the rate of disease progression. Lorenzo’s oil is not a substitute for stem cell transplant or gene therapy in boys with active cerebral disease, but it remains a consideration for asymptomatic boys as part of a monitoring strategy.