X-linked adrenoleukodystrophy is a genetic disorder that mainly affects the nervous system and the adrenal glands, which are located on top of each kidney. In this disorder, the fatty covering (myelin) that insulates nerves in the brain and spinal cord tends to deteriorate (a condition called demyelination). The loss of myelin reduces the ability of the nerves to relay information to the brain. In addition, damage to the outer layer of the adrenal glands (adrenal cortex) causes a shortage of certain hormones (adrenocortical insufficiency). Adrenocortical insufficiency may cause weakness, weight loss, skin changes, vomiting, and coma.

There are four distinct types of X-linked adrenoleukodystrophy: a childhood cerebral form, an adrenomyeloneuropathy type, an adrenal insufficiency only form, and a type called asymptomatic.

The childhood cerebral form of X-linked adrenoleukodystrophy typically occurs in boys. Girls are rarely affected with this type. If not treated, affected boys experience learning and behavioral problems that usually begin between the ages of 4 and 10. Over time the symptoms can worsen, and children may have difficulty reading, writing, understanding speech, and comprehending written material. Additional signs and symptoms of the cerebral form include aggressive behavior, vision problems, difficulty swallowing, poor coordination, and impaired adrenal gland function. The rate at which this disorder progresses is variable but can be extremely rapid, often leading to total disability within a few years. The life expectancy of individuals with this type depends on whether early diagnosis and treatment are available. Without treatment, individuals with the cerebral form of X-linked adrenoleukodystrophy usually survive only a few years after symptoms begin.

Signs and symptoms of the adrenomyeloneuropathy type appear between early adulthood and middle age. Affected individuals develop progressive stiffness and weakness in their legs (paraparesis), experience urinary and genital tract disorders, and often show changes in behavior and intellectual function. Most people with the adrenomyeloneuropathy type also have adrenocortical insufficiency. Some severely affected individuals develop cerebral X-linked adrenoleukodystrophy.

People with X-linked adrenoleukodystrophy whose only symptom is adrenocortical insufficiency are said to have the adrenal insufficiency only form. In these individuals, adrenocortical insufficiency can begin anytime between the first year of life and adulthood. However, most affected individuals develop the additional features of cerebral X-linked adrenoleukodystrophy in childhood or the adrenomyeloneuropathy type by the time they reach middle age. The life expectancy of individuals with the adrenal insufficiency form depends on the severity of the signs and symptoms, but typically this is the mildest of the three types.

Children with the asymptomatic form do not appear to have any symptoms of X-linked adrenoleukodystrophy, but medical testing may show brain or biochemical abnormalities. Some individuals with the asymptomatic form may develop features of other types of X-linked adrenoleukodystrophy later in life.

Rarely, individuals with X-linked adrenoleukodystrophy develop multiple features of the disorder in adolescence or early adulthood. In addition to adrenocortical insufficiency, these individuals usually have psychiatric disorders and a loss of intellectual function (dementia). It is unclear whether these individuals have a distinct form of the condition or a variation of one of the previously described types.

For reasons that are unclear, different forms of X-linked adrenoleukodystrophy can be seen in affected individuals within the same family.

Variants (also known as mutations) in the ABCD1 gene cause X-linked adrenoleukodystrophy. The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP), which is involved in transporting certain fat molecules called very long-chain fatty acids (VLCFAs) into peroxisomes. Peroxisomes are small sacs within cells that process many types of molecules, including VLCFAs.

ABCD1 gene variants result in a shortage (deficiency) of ALDP. When this protein is lacking, the transport and subsequent breakdown of VLCFAs is disrupted, causing abnormally high levels of these fats in the body. The accumulation of VLCFAs may be toxic to the adrenal cortex and myelin. Research suggests that the accumulation of VLCFAs triggers an inflammatory response in the brain, which could lead to the breakdown of myelin. The destruction of these tissues leads to the signs and symptoms of X-linked adrenoleukodystrophy.

Normal Function

The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP). ALDP is located in the membranes of cell structures called peroxisomes. Peroxisomes are small sacs within cells that process many types of molecules. ALDP brings a group of fats called very long-chain fatty acids (VLCFAs) into peroxisomes, where they are broken down.

Health Conditions Related to Genetic Changes

X-linked adrenoleukodystrophy

More than 650 mutations in the ABCD1 gene have been found to cause X-linked adrenoleukodystrophy. This condition is characterized by varying degrees of cognitive and movement problems as well as hormone imbalances. The mutations that cause X-linked adrenoleukodystrophy prevent the production of any ALDP in about 75 percent of people with this disorder. Other people with X-linked adrenoleukodystrophy can produce ALDP, but the protein is not able to perform its normal function. With little or no functional ALDP, VLCFAs are not broken down, and they build up in the body. The accumulation of these fats may be toxic to the adrenal glands (small glands on top of each kidney) and to the fatty layer of insulation (myelin) that surrounds many nerves in the body. Research suggests that the accumulation of VLCFAs triggers an inflammatory response in the brain, which could lead to the breakdown of myelin. The destruction of these tissues leads to the signs and symptoms of X-linked adrenoleukodystrophy.

Other Names for This Gene

• ABCD1_HUMAN
• ALD
• ALDP
• AMN
• ATP-binding cassette, sub-family D (ALD), member 1

Genomic Location

X-linked adrenoleukodystrophy (X-ALD) is inherited in an X-linked manner. This means that the ABCD1 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes. Each woman has two X chromosomes, and each man has one X chromosome and one Y chromosome. Because men have only one X chromosome, they only have one copy of the ABCD1 gene. If this gene has a disease-causing change, they will have X-ALD.

Women who have disease-causing changes in one copy of the ABCD1 gene are known as carriers of the disease. About 80% of carriers do not have signs or symptoms of X-ALD because they have another working copy of ABCD1. However, about 20% of female carriers have symptoms that are similar to the adrenomyeloneuropathy (AMN) type of X-ALD.

If a male is diagnosed with X-ALD, it is likely that his mother is a carrier of the disease. However, about 5% of cases of X-ALD are caused by a new genetic change (de novo) in the individual. In these situations, the mother is not a carrier of the disease, and other family members are not at risk to have children with X-ALD. Therefore, when a male is diagnosed with X-ALD, it is important to determine if his mother is a carrier by testing her VLCFA levels or by genetic testing.

If a woman is found to be a carrier of X-ALD, for each of her children there is a 50% chance that he or she will inherit the change in ABCD1. This means that for each son, there is a 50% chance that he will be affected with X-ALD. For each daughter, there is a 50% chance that she will be a carrier of the disease like her mother.

X-ALD shows a characteristic known as variable expressivity. This means that the exact symptoms of each person with X-ALD can differ, even within the same family. For example, some boys may have the childhood cerebral form of X-ALD, while other members of the same family may have the adrenal insufficiency-only type. It is not known what causes variable expressivity of the disease to occur. The symptoms cannot be predicted by levels of VLCFA or by looking at the exact genetic change (mutation) in each individual.

Signs and symptoms of X-ALD typically do not appear until childhood (as early as 2 years old, but more commonly between 4 and 10 years old). While there are no treatments yet that prevent these signs, monitoring can help catch and treat changes right away.

Signs of the condition in the adrenal gland may include the following:

• Vomiting
• Decreased appetite
• Darker skin color
• Low blood sugar (hypoglycemia)
• Getting sicker than would be expected with an infection

Signs of the condition in the nervous system may include the following:

• Hyperactivity
• Difficulties in maintaining attention
• Aggressive behavior
• Seizures
• Muscle weakness
• Poor coordination and motor control
• Difficulty swallowing
• Vision problems
• Hearing loss
• No longer being able to do things they could do before (milestone regression)

X-linked adrenoleukodystrophy (X-ALD) is suspected when a doctor observes signs and symptoms of the disease. X-ALD should be considered as a possible cause of symptoms in four situations:

• Boys with attention deficit disorder (ADD) who also have signs of neurological problems
• Young men with progressive trouble walking or coordinating movements
• All males with adrenal insufficiency (Addison disease), even in the absence of other symptoms
• Adult women with progressive muscle weakness or wasting

If a diagnosis of X-ALD is suspected, a blood test of very long-chain fatty acids will detect elevated levels in 99% of males. Genetic testing can be used to confirm the diagnosis. After diagnosis, a brain MRI can be completed to determine the extent of the disease. A brain MRI will be abnormal even if symptoms of the disease are not very severe.

Newborn screening for X-ALD is done using a small amount of blood collected from your baby's heel. During screening, a special machine measures the level of very long chain fatty acids in your baby's blood. Babies with high levels of these substances might have X-ALD. In some cases, elevated VLCFA levels require a second test. This second test looks for changes in the gene that causes X-ALD (called ABCD1). Newborn screening cannot tell what type of X-ALD a baby will have.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for X-ALD is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition are rare. Babies with other conditions that have elevated very long chain fatty acids may also be detected through this screening. An example of another condition that may be detected is Zellweger Spectrum Disorder.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

Treatments may include the following:

• Regular monitoring of the nervous system (using magnetic resonance imaging [MRI]) and of the adrenal gland (using special blood tests)
• Hormone replacement therapy if the adrenal glands are not functioning well. This is usually a pill taken several times daily.
• Stem cell transplantation, if the cerebral (brain) form of the condition is present
• Medicines for certain symptoms (e.g., stiffness and seizures)
• Physical therapy
• Additionally, new and investigational therapies may be available through research based clinical trials.

Children who receive early and ongoing treatment for X-ALD can have better health outcomes than those who do not. Early stem cell transplantation can help prevent problems in children with nervous system symptoms. Treatment works best if it is given when changes are just beginning in the brain, before it becomes extensive and nervous system signs or symptoms start.

The long-term outlook for people affected by X-linked adrenoleukodystrophy (X-ALD) depends on the exact type of the disease that each person has. The childhood cerebral form of the disease is progressive. Boys with this form of the disease often pass away within a few years of beginning to show symptoms. The other forms of X-ALD are less severe. The disease for these individuals may be slowly progressive, or it may not affect a person’s lifespan at all.

It is important to remember that the exact signs and symptoms of a person with X-ALD cannot be predicted by the signs and symptoms of other members of the family. Therefore, the long-term outlook for individuals who have X-ALD within the same family can be very different.