ALD is a multisystem disease, but most prominently affects both the central and peripheral nervous systems, which are responsible for all of the body’s voluntary and involuntary functions.
Damage to the brain results in blindness, seizures and hyperactivity. Other effects include problems with speaking, listening, and understanding verbal instructions.
Damage to the spinal cord results in the loss of the ability to walk and maintain normal breathing.
The most severely affected tissues outside of the nervous system are the adrenal cortex, and the Leydig cells in the testes. Damage to the adrenal cortex results in adrenal insufficiency or Addison’s Disease. Damage to the testes results in infertility.
The rate of progression depends on what form of the disease the individual has.
With proactive, comprehensive medical care the symptoms of ALD can be managed and give the individual the best quality of life possible. Furthermore, through ALD newborn screening, affected children have the opportunity to benefit from lifesaving treatment.
Why does the disease typically impact boys?
The damaged gene that causes ALD resides on the X Chromosome. Boys inherit only one X Chromosome, which is passed to them from their mothers. Because girls inherit two X Chromosomes, one from each parent, the functional copy inherited from their father usually protects female children from the disease. However, females with the mutation are carriers who can pass the disease on to their male offspring. It is possible – but rare for girls to inherit 2 copies of the mutation from both parents.
Could other children in the family also have ALD?
Yes, if a mother has ALD, there is a 50% chance of each of her other children also having ALD. This is crucial if the child is male and they should be tested immediately. If there are other female children they can be tested when they are of childbearing age. Extended family – sisters, brothers, aunts, uncles, nieces, and nephews of the affected parent should also be tested for ALD.
To determine if other children in the family are affected by or carriers of ALD disease, it is best to consult with your genetic counselor or your child’s physician.
Are women only carriers or do they have ALD?
In some females, known as heterozygotes, who inherit a single copy of the disease gene for ALD, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit symptoms associated with ALD.
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.
What is myelin (white matter) and why is it so important in the nervous systems?
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 (see Treatment Section).
What is the prevalence of ALD?
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. The condition occurs throughout the world in all ethnic groups.
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).
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.
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.