Frequently Asked Questions

Adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the adrenal glands and the nervous system. It results from mutations in the ABCD1 gene, leading to the buildup of very long-chain fatty acids in the body. This accumulation damages the myelin sheath, which protects nerve cells, causing a range of neurological and physical symptoms.

ALD is caused by the mutation of a single gene named ABCD1. That gene makes a protein that helps break down very long chain fatty acids (VLCFAs) that are naturally present in the human body and also introduced through diet. This chemical breaking-down process provides the body with energy. Because this particular gene is defective and does not correctly make the required protein, above average levels of these fatty acids build up in patients’ blood and organ tissue.

When the VLCFAs build up in the central nervous system, they can eventually destroy the myelin sheath—the protective, insulating coating—that surrounds the nerves. If this occurs in the brain, it often leads to neurologic problems, while in the spinal cord, it can lead to difficulty walking. VLCFAs are also toxic to adrenal gland cells. The toxicity leads to those cells malfunctioning, which then causes adrenal insufficiency.

ALD is diagnosed through a combination of clinical evaluation, family history, and genetic testing. Newborn screening programs can identify ALD early, even before symptoms appear. If ALD is suspected, a healthcare provider may recommend further diagnostic tests, including blood tests for very long-chain fatty acids and genetic testing to confirm the diagnosis.

ALD is associated with a build up of very long-chain fatty acids (VLCFAs) and most prominently affects the adrenal glands and myelin sheath, which is a protective coating for nerve cells. Adrenal glands are commonly damaged in boys with ALD, leading to adrenal insufficiency. Sometimes, damage occurs to myelin in the brain of boys with ALD, which leads to cerebral ALD. If left untreated, cerebral ALD can lead to severe neurological damage, but life-saving treatments are available if the disease is caught early enough. Damage to myelin in the spinal cord often occurs in adults with ALD and can lead to difficulty in walking among other symptoms. Individuals with ALD can experience a variety of symptoms, or none at all.

Generally, ALD patients are divided into different groups based on their phenotypes, or common shared traits. The categories are generally considered to be: asymptomatic, adrenal insufficiency, cerebral ALD, adreomyeloneuropathy (AMN), and (a)symptomatic women with ALD. Each phenotype is associated with different, but sometimes overlapping symptoms and can range in severity from mild to severe depending on the individual affected. Symptoms of ALD can vary widely depending on the type and stage of the disease. Common symptoms include behavioral changes, cognitive decline, problems with motor skills, and adrenal insufficiency. In some forms, symptoms may develop in childhood, while others may emerge in adulthood.

ALD is a single gene disorder, which means that ALD is always caused by a genetic mutation in one gene, called ABCD1. The non-functional gene is usually inherited from a parent, however ALD can sometimes occur via spontaneous mutation without any family history, which is also called a de novo mutation. Once a person has ALD, they are at risk for passing the disease to their children. The inheritance pattern for ALD differs depending on whether the affected parent is a male or female, because the ABCD1 gene is located on the X chromosome. Typically, males have one X-chromosome and one Y-chromosome (XY), while females have two X-chromosomes (XX).

If a mother has ALD, she usually has one X chromosome with a functional ABCD1 copy and one X chromosome with a non-functional ABCD1 copy. Whether or not her child is a boy or girl, she passes one of her two X chromosomes to her child. Therefore, a mother with ALD has a 50% chance that each child, regardless of sex, will inherit the non-functional ABCD1 gene and have ALD themselves.

If a father has ALD, typically the only X chromosome he has contains the defective ABCD1 gene. When males have children, they always pass their only X chromosome to all of their daughters and their only Y chromosome to all of their sons. Therefore, a man with ALD or AMN has a 0% chance that any of his sons will inherit his ALD and a 100% chance that each of his daughters will inherit ALD.

The damaged gene, ABCD1, that causes ALD resides on the X chromosome. Boys inherit only one X chromosome, which is passed to them from their mothers. Girls inherit two X chromosomes, one from each parent. Girls typically inherit one functional ABCD1 gene from their unaffected parent, which usually protects female children from the disease, but is not enough to protect women from developing symptoms as they age.

Yes, many women with ALD experience symptoms, particularly as they age. Although women typically inherit one functional copy of the ABCD1 gene from their unaffected parent, some cells in their bodies still try to use the non-functional ABCD1 copy due to a process called X-inactivation. Symptoms in women can be mild to severe depending on the individual, and often include difficulty walking, neuropathy, and bowel and bladder dysfunction. See the “Symptomatic Women” page for more information.

Yes, ALD is caused by a genetic mutation, so it often runs in families. See “How do you get ALD?” above for information about how ALD is inherited. It is a good idea to talk to your genetic counselor or doctor about what other family members might be at risk for ALD. This is especially time-sensitive if there are young boys in the family who could be at risk for developing cerebral ALD.

Depending on the inheritance of ALD in your family, certain immediate and extended family members will be at risk for ALD and should be offered testing. Talk to your genetic counselor or 6doctor to figure out who is at risk, and consider sharing the diagnosis with extended family members so they can seek testing.

Genetic testing, which looks for a mutation (also known as a variant) in the ABCD1 gene, is considered the gold standard for ALD diagnosis. Talk to your doctor or genetic counselor to start the genetic testing process and for help understanding the results. Genetic testing will identify the specific variant in your family (i.e. how the spelling of the ABCD1 gene is changed in your family). If a variant is found in the ABCD1 gene that is known to cause disease or is very likely to cause disease, it will be considered “pathogenic” or “likely pathogenic”, which will confirm the diagnosis of ALD.

Sometimes, a variant will be detected in the ABCD1 gene that has not been seen before in symptomatic patients with ALD, and there is not enough evidence to yet know if this variant will disrupt the function of the gene and be “pathogenic”, or if it will result in no functional consequence to the gene and be a “benign” variant. These variants with inadequate information will be called “Variants of Uncertain Significance (VUS)”, meaning it is unclear from the genetic information alone whether they will cause ALD. In the case of VUSes, it is particularly important to consider whether the patient has any symptoms and whether their biochemical markers are elevated (see below) to establish an ALD diagnosis. Due to the serious consequences of ALD manifestations, particularly adrenal insufficiency and cerebral ALD in boys, it is important that children with a VUS in the ABCD1 gene still undergo routine monitoring for ALD.

Traditional biochemical testing for ALD consists of fasting very long-chain fatty acid (VLCFA) testing. VLCFA testing measures the levels of VLCFAs in the plasma, and is very accurate for males with ALD and AMN, who have elevated levels of VLCFAs. This test can also be conducted on women, however 15% of women with ALD will have normal VLCFA levels, resulting in a “false negative” result.

More recently, an updated biochemical biomarker has become available for testing, known as C26:0-lysophosphatidylcholine (C26:0-lysoPC), which is extremely accurate in both men and women with ALD. In contrast to VLCFA testing, C26:0-lysoPC testing will detect more than 99% of women with ALD, and is thus considered more accurate, especially for women.

Newborn screening is a screening test conducted with dried blood spots taken from a baby just after birth. In many states, ALD is included on the newborn screening panel, and babies are screened for ALD using a modified VLCFA test. If a baby screens positive for ALD, they will have confirmatory diagnostic testing before being officially diagnosed with ALD.

Myelin constitutes the “white matter” of the brain. It consists of fatty acid molecules, and provides the protective covering of the nerve cells, similar to insulation surrounding an electric wire. Myelin is required for the rapid, precise transmission of information to and from neurons throughout the brain and spinal cord. Demyelination is the stripping away of the fatty coating (white matter) that keeps nerve pulses confined and maintains the integrity of nerve signals. This process inhibits the nerves’ ability to conduct properly, thereby causing neurological deficits. In childhood cerebral ALD, not only do cells undergo demyelination, but there is also an inflammatory response, all of which destroy the brain.

When myelin is damaged, communication is lost during transmission. This results in the loss of voluntary and involuntary functions in the body.

Currently, there is no known treatment to reverse damaged myelin, although there are options to manage symptoms. Proactive, comprehensive medical care will allow families and caregivers to give the affected individual the best quality of life possible. Furthermore, through ALD Newborn Screening, affected children have the opportunity to benefit from lifesaving treatment, which can halt the disease.

The prevalence of ALD is estimated to be between 1 in 10,000 and 1 in 17,000 individuals in the general population. Prevalence refers to the number of people in the general population who have a disorder at any given time. Rare disorders like ALD often go undiagnosed or misdiagnosed making it difficult to determine the true frequency of the disorder in the general population, but the adoption of newborn screening for ALD is beginning to give us a better look at the true prevalence. The condition occurs throughout the world in all ethnic groups.

Adrenal insufficiency is typically managed with daily steroid replacement pills to replace the hormones that the body is not properly making due to damaged adrenal glands.

For the most serious phenotype, childhood cerebral ALD, there are potentially lifesaving procedures available. In boys and adolescents with early-stage cerebral ALD, an allogeneic hematopoietic stem cell transplantation (HSCT) can stop the progression of the degradation of the myelin in the brain if the procedure is performed at a very early stage of the disease. After intensive chemotherapy, allo-HSCT relies on bone marrow stem cells from another person who “matches” the patient. The procedure aims to use the donor-derived cells to produce the ABCD1 protein that the recipient is incapable of making.

Gene therapy is another type of stem cell transplant that uses the patient’s own cells as a therapy. In gene therapy for ALD, a patient’s cells are removed from the body, modified to produce a functional ABCD1 protein, and then transplanted back into the body. This is called an autologous transplant. Gene therapy was recently approved by the FDA for boys with cerebral ALD. Both allo-HSCT and gene therapy are potentially life-saving treatments, but both treatments come with risks that should be carefully evaluated and discussed with a team of medical professionals.

There are currently no specific treatments for the adult spinal cord manifestation of the disease, so treatment is typically aimed at managing symptoms. However, there are clinical trials currently ongoing for adult patients. See our Clinical Trials page or clinicaltrials.gov for more information.

Please email us at [email protected]. We are here to provide assistance and answer any inquiries you may have about ALD.