What is ALD?

Adrenoleukodystrophy (ALD) is a progressive, genetic disease that affects the adrenal glands, the spinal cord, and the white matter (myelin) of the nervous system. ALD is considered a rare disease, and affects approximately 1 in 15,000 people worldwide.

What are the symptoms of ALD? How does it progress?

ALD symptoms can vary depending on age, gender, and the body tissues affected. The tissues that are most severely affected in ALD are myelin, blood, and the adrenal glands. Not all tissues are affected at the same time.

In the world of genetic disorders, doctors group collections of symptoms into “phenotypes” based on the cells and tissues that are most severely affected by a gene abnormality. Individuals with the ALD gene may have different phenotypes. A person may experience several phenotypes throughout their life. In fact, it is common for individuals to have more than one phenotype at any given time.

There are 4 primary phenotypes that can occur in males with the ALD gene:

  1. Asymptomatic (meaning no symptoms)
  2. Adrenomyeloneuropathy (AMN),
  3. Adrenal insufficiency, and
  4. Cerebral demyelinating ALD (cerebral ALD)

Asymptomatic phenotype

Most individuals with the ALD gene are free of clinical symptoms for at least the first three years of life. ALD does not cause developmental delay. Some individuals continue to have no symptoms for many years. But as the diagram shows below, the percentage of asymptomatic men and women decreases with age.

Adrenal insufficiency (Addison’s disease)

Adrenal insufficiency occurs as a result of permanent injury to the adrenal glands. More than 80% of men with ALD will eventually develop adrenal insufficiency over their lifespan. Adrenal insufficiency is very uncommon in women with ALD. Adrenal insufficiency is sometimes referred to as Addison’s disease, named for Dr. Thomas Addison, who first described it. Symptoms can include weakness/fatigue, nausea, abdominal pain, and low blood pressure. These symptoms can have many different causes and therefore are often not recognized to be due to adrenal insufficiency. Some symptoms such as darkening of the skin are a more obvious sign of adrenal insufficiency. Because of the high rates of adrenal insufficiency in the male population, testing for insufficiency is extremely important, and an endocrinologist should be consulted. Although it is easily treatable with oral medications, adrenal insufficiency can be life-threatening if it is not recognized quickly. Patients and caretakers should educate themselves about the importance of stress-dosing steroids with illnesses and major injuries.

Adrenomyeloneuropathy (AMN)

The AMN phenotype occurs in about 45% of people with ALD and generally develops in adults. AMN affects the longest nerve fibers of the spinal cord. These fibers conduct signals from the brain to the legs and the bladder and back to the brain. Some people experience some of the following symptoms:

Cerebral demyelinating ALD

Unlike AMN, childhood cerebral adrenoleukodystrophy (cerebral ALD) is a rapid and often fatal disease that mostly affects boys between the ages of 4-10 years. Affected boys’ symptoms may include “spacing out” in school: inattention, deterioration in handwriting skills, and decreased school performance; difficulty in understanding speech (though sound perception is normal); difficulty in reading and understanding written material; clumsiness; visual disturbances and occasionally double-vision; and aggressive or unexplained inappropriate behavior. In some boys, seizures may be the first symptom. Symptom severity varies from patient to patient and is not determined by phenotype. Even identical twins may have different experiences with symptom onset and severity.
Although less common, teenage and adult males may also develop the cerebral variant of ALD. In adults, the first symptoms are often psychiatric and can resemble depression or psychosis. Additional symptoms may include hearing and visual impairment, problems with coordination, and seizures. Adult men should have an MRI once a year to ensure there is no demyelination occurring in the brain. For young children, an MRI should be done every six months because brain inflammation can be silent and move more quickly in children. The early discovery of brain inflammation increases the chance for success of lifesaving intervention.

The following diagram shows the risk of different phenotypes depending on a person’s age.

Fig 2: The diagram shows that the phenotype can change over time. A male who has symptoms associated with a particular phenotype may later develop other symptoms associated with another phenotype. For example, and as the diagram shows, men around 45 years’ old will likely develop both adrenal insufficiency and AMN symptoms. Unfortunately, there is no test that can predict how the disease will progress in a person over time.

There are 2 primary phenotypes that can occur in females with the ALD gene:

  1. Asymptomatic
  2. Adrenomyeloneuropathy (AMN)

Adrenal insufficiency and cerebral ALD rarely affect women, but women may experience AMN symptoms. However, AMN is less severe and develops later in women.

What causes ALD?

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 eventually destroy the myelin sheath—the protective, insulating coating—that surrounds the nerves. This often leads to neurologic problems. VLCFAs are also toxic to adrenal gland cells. The toxicity leads to those cells malfunctioning, which then causes adrenal insufficiency.

A 10 minute overview of ALD


Produced by Youreka Science in collaboration with ALD Connect, Inc.

Are there any treatments?

There currently is no cure for ALD in any of its symptomatic forms.

However, for the most serious phenotype, childhood cerebral ALD, there are potentially lifesaving procedures available. In boys and adolescents with early-stage cerebral ALD, 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, 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 protein that the recipient is incapable of making. Unfortunately, this procedure comes with a significant amount of risk. Infections, graft versus host disease, and other complications can be life threatening. HSCT can be lifesaving, but it is not a cure. Research suggests that patients who undergo HSCT as a child may still develop signs of AMN in adulthood.

Gene therapy offers a promising therapy to stop the progression of demyelination without some of the risks HSCT presents. Currently in a Phase 2/3 clinical trial, bluebird bio, inc. has reported successful outcomes. A video produced by bluebird bio explains how gene therapy works:

How do you get ALD?

ALD is called an X-linked disorder, which means that the ALD gene (ABCD1) is located on the X-chromosome. Men have one X-chromosome and one Y-chromosome (XY). When the father is carrying the defective ALD gene, there is no other X-chromosome for protection; therefore, he will experience ALD symptoms. Women have two X-chromosomes (XX).

 

Fig 4: (Left) If a woman is a carrier for the defective ALD gene she has the following possible outcomes with each newborn: when the child is a daughter, there is a 50% chance that the daughter receives the defective ALD gene and a 50% chance that the daughter is unaffected. In case the child is a boy, there is a 50% chance that the son has ALD and a 50% chance that he will be unaffected. (Right) For an X-linked disorder, such as ALD, if an affected man has children, then all of his sons will be free of the disease, since the father always passes his Y-chromosome on to his sons. However, all of his daughters will inherit the defective ALD gene (he always passes his only (affected) X-chromosome on to his daughter).

Who should be tested for ALD?

With more and more states adding ALD to their newborn screening panels, the medical community will be able to identify ALD patients sooner, which will translate into better care and lives saved. But newborn screening also identifies family members who potentially carry the ALD gene. If a family member has been identified as a patient or an ALD carrier, additional testing of extended family should take place as well because they too may be a carrier and ultimately affected.

Depending on the affected person’s gender, family relationship, and the carrier status of the affected person’s parents, aunts, uncles, and cousins may be at risk of being carriers or being affected.

Testing of at-risk female relatives for carrier status is a two-step process. Measurement of plasma concentration of VLCFA is performed first; if abnormal, the female is affected. Because around 15% of women with ALD have normal plasma concentration of VLCFA, molecular genetic testing should be used to test those females with a normal concentration. Your doctor or genetic counselor, can suggest commercial companies that can perform the required genetic testing.