Adrenoleukodystrophy (ALD)

ALD is caused by a mutation in the ABCD1 gene on the X chromosome, but it can be inherited from either or both parents. The reason that the disease primarily affects males is because they only have one X chromosome, whereas women who inherit this faulty gene still have a second X chromosome to offset the mutation. Pregnant women who carry the ALD mutation on an X chromosome have a 50–50 chance of passing it on—either a son potentially affected by the disease or a daughter who also carries the mutation on one X chromosome. 

The mutation on the ABCD1 gene prevents the body from breaking down very-long-chain fatty acids (VLCFAs). These acid chains then accumulate in the brain, nervous system, and adrenal bland, which is thought to cause inflammation. This inflammation damages the myelin sheaths surrounding nerve fibers, leading to increasingly serious symptoms. 

The most significant risk factor for ALD is having a genetic history of the disease. Otherwise, the risk of ALD is the same regardless of a person’s race, ethnicity, or geographical location.

ALD symptoms may develop later in life, but more often the disease is diagnosed when boys between the ages of 4 and 10 begin showing the following signs: 

• Behavioral problems 

• Withdrawal or aggression 

• Poor memory 

• Poor school performance 

• Difficulty reading, writing, and understanding speech 

As more myelin is lost, the symptoms worsen and include: 

• Vision problems 

• Seizures 

• Difficulty swallowing 

• Deafness 

• Poor coordination and balance 

• Inability to speak or respond 

Other symptoms include: 

• learning disabilities 

• fatigue 

• intermittent vomiting 

• weight loss 

• lack of appetite 

• nausea 

• darkening of the skin 

• progressive dementia 

• muscle weakness 

• low blood sugar 

• headaches in the morning 

ALD that begins in childhood and progresses to a more severe phase is sometimes referred to as CALD, cerALD, or cerebral ALD. This differentiates it from three other types: 

• Adrenal insufficiency, also called Addison’s disease. This disease develops when the adrenal glands fail to produce enough cortisol. 

• Adrenomyeloneuropathy (AMN), a form of ALD affecting the nerves and spinal cord, typically in adults. This type of ALD progresses slowly over decades. 

• Asymptomatic ALD, which is when people have a mutation in the ABCD1 gene but no symptoms. 

It is also possible for a person to have more than one type of ALD. 

Because of the “X-linked” chromosomal nature of ALD, it is very unlikely for girls to be affected by childhood cerebral ALD. However, in adulthood, about half of the women carrying this mutation may develop milder neurological symptoms due to AMN—specifically progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, and urinary problems. 

If a patient presents signs or symptoms of ALD, the first step is typically to evaluate the individual’s medical history thoroughly. If doctors think the patient might have ALD, they will then request additional testing, beginning with a blood test to measure levels of VLCFA. High levels are indicative of ALD, but a genetic test is needed to confirm a diagnosis. This test can accurately identify the ABCD1 mutation and point to other family members who may be affected. Many U.S. states have added ALD screening for newborns. This screening is important, because without it, ALD can be misdiagnosed as a behavioral or developmental issue. 

Especially for childhood cerebral ALD, early diagnosis is critical. This is because the disease progresses rapidly, and there is a narrow window of opportunity to prevent neurological damage or replace lost myelin. Boys who have been diagnosed with ALD should have regularly scheduled MRIs so that doctors can monitor the disease. 

Fortunately, treatments exist for ALD. Medications and therapy (such as physical, occupational, or speech therapy) can be used to treat the symptoms of the disease. But there are also some newer treatments that focus on the central genetic problem within patients’ cells, though currently they are costly, risky, and not widely available. 

If ALD is diagnosed early enough (before neurologic symptoms develop or while they are still very mild), the disease can be treated with gene therapy or stem cells. Gene therapy can halt the decline in brain function in cerebral ALD and enable children to thrive. A stem-cell transplant from a genetically matched donor can stop ALD progression. Both methods have some inherent risks that should be discussed in advance with the care team, and each requires initial chemotherapy to make room for new blood cells in patients’ bone marrow. 

Boston Children’s and Massachusetts General Hospital have developed a recently FDA-approved gene therapy treatment called SKYSONA for boys with ALD who are experiencing few or no symptoms. It also incorporates stem cells, taken from the patient’s own blood and treated in a lab to replace the defective or missing ABCD1 gene, thus restoring their ability to break down VLCFAs. 

The Stop ALD Foundation, an advocacy group focused on ALD and finding cures, provides regular updates on ongoing ALD research efforts and clinical trials. Some other ideas being explored include ALDR upregulation (in which the activity of another gene might be increased to compensate for ABCD1’s deficiencies) and either transplanting cells or administering drugs to aid in myelin restoration. Currently, a drug called leriglitazone is showing some promise for halting the progression of ALD in early stages, but studies continue. 

Research funded through the american brain foundation

Dr. Danielle Kim, a 2025 Next Generation Research Grant recipient, is currently undertaking a study on cerebral ALD. Specifically, she is conducting research to determine if vitamin D could be used as a preventative therapy for cerALD. She posits that if vitamin D could improve blood flow and levels of certain antioxidants in the brain, this low-cost intervention might be able to prevent fatal brain lesions. This research is funded by Arrivederci ALD through the American Brain Foundation, in collaboration with the American Academy of Neurology.

Learn more about research funded by American Brain Foundation donors >

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