Adrenoleukodystrophy (X-ALD) is a deadly disease which affects the white matter of the brain and the adrenal glands. Most people are familiar with this disease from the movie "Lorenzo's Oil." For many years it was thought that women were only carriers of X-ALD. However, scientists found that approximately 20 % of the female carriers of (X-ALD) develop neurological symptoms. Decreased feeling in the legs have been the most common complaint. Now there are six types of Adrenoleukodystrophy, one of which is the kind which affects women.
The adrenal glands are important to life. A person can die if they are diseased or damaged. A woman can become infertile if the adrenals aren't working properly, or at the very least suffer some very uncomfortable symptoms.
Don't just take over the counter medicine for "adrenal fatigue." See a doctor. Your life is too important to trust it to chance.
Adrenoleukodystrophy: A rare disorder which has characteristic symptoms of Addison disease (adrenocortical insufficiency) and Schilder disease (cerebral sclerosis). Bronze skin, brain sclerosis and demyelination are the main symptoms. Other symtoms include:
•Impaired motor function
•Difficulty reading in children
•Difficulty writing in children
•Difficulty understanding speech in children
•Difficulty comprehending written material in children
•Increased skin pigmentation
•Lack of control of voluntary leg movements
•Muscle weakness on one side of body
•Reduced hormone production by testes
•Reduced hormone production by ovaries
What are ALD and AMN?
Adrenoleukodystrophy (ALD) describes any of several closely related inheritable disorders that affect the adrenal glands, nervous system, and testes. Adrenoleukodystrophy is transmitted as an X-linked trait (the neonatal form is by autosomal recessive transmission and is a different disease). It results in the accumulation of long chain fatty acids in the nervous system, adrenal gland, and testes. The childhood cerebral form appears in mid-childhood (at 4-8 years), and the other forms appear during adolescence.
In the childhood form, early symptoms include hyperactivity, difficulty at school, difficulty understanding spoken material, deterioration of handwriting, crossed eyes (strabismus), and possibly seizures. As the disease progresses, further signs of damage to the white matter of the brain appear; they include changes in muscle tone, stiffness and contracture deformities, swallowing difficulties, and coma.
The other major component of adrenoleukodystrophy is the development of impaired adrenal gland function (similar to Addison disease). There is a deficiency of steroid hormones. This is a very significant development but one that can be adequately treated with corticosteroids. (Adapted from Medline Plus Medical Encyclopedia)
Adrenomyeloneuropathy (AMN) is a disorder of adult males, consisting of long standing adrenal insufficiency, hypogonadism, progressive myelopathy, peripheral neuropathy, and sphincter disturbances; considered a variant of adrenoleukodystrophy. (Adapted from Online Medical Dictionary.)
A child in our family has been diagnosed with ALD: What should we do? What do we need to know?
A child in our family was just diagnosed with ALD, what are the first things we should do?
Get a magnetic resonance imaging (MRI) scan of the child’s brain. This will tell you the extent of the progression of the disease, and determine next steps. It will also provide a baseline for you and physicians to use to compare with future MRI scans, which are generally performed at 6 – 12 month intervals.
Have your child tested for adrenal insufficiency (Addison’s disease). This is usually done by a pediatric endocrinologist. Addison’s disease is generally associated with ALD. The adrenal glands produce a variety of hormones that control levels of sugar, sodium, and potassium in the body, and help it respond to stress. In Addison’s disease, the body produces insufficient levels of the adrenal hormone, which can be life-threatening. Fortunately, this aspect of ALD is easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness).
Consider limiting your child’s fat intake to no more than 30% of his daily diet. This is easily done by limiting red meats and using low-fat substitutes for things like milk and butter
If your child is between the ages of 2 and 6 years old and is not yet symptomatic, you may consider participating in a clinical research trial. There is only one currently underway, at the Kennedy Krieger Institute in Baltimore, Maryland. It uses a combination of a low-fat diet and “Lorenzo’s oil” to stave off the onset of symptoms. Lorenzo’s oil is not a cure for ALD, but recent findings from the ongoing studies at Kennedy Krieger have shown that it may have promise in keeping children symptom-free. You can contact the Institute about trial enrollment by calling +1 (443) 923-2750.
If your child already has symptoms, the only currently approved treatment for ALD is a stem cell transplant, using either stem cells derived from bone marrow or from umbilical cord blood (UCB). If done early enough, this treatment has been found to stop the neural degeneration. However, both types of transplantation are risky procedures that can also be life-threatening. Research shows that this treatment has its best chance of success when the child has no more than one diagnosed neurological deficits, and a Loes score of 9 or lower.
Will gene therapy or stem cell transplant save our child’s life?
Gene therapy is not yet available outside the confines of a very small, preliminary clinical trial in France. Stem cell transplantation, either using umbilical cord blood stem cells or bone marrow stem cells from a matched donor, has been used successfully to arrest the progress of ALD in some boys with the disease. The treatment has serious risks of its own. Because the body’s immune system must essentially be shut down by high-dose chemotherapy and/or radiation to prevent rejection of the “foreign” transplanted cells, the child is at risk from even the smallest cold or other infection. Statistics show that the mortality rate after such transplants can be as high as 40%. The disease also can progress for six to eighteen months post transplant—meaning that the child will lose some additional brain function before improving, even if the transplant is successful.
However, for boys who are candidates for a transplant, it is currently the only option to halt the disease’s destruction of brain cells. Transplantation must be considered very carefully; there are no easy answers.
A child in our family has ALD. How do we know if he is a candidate for transplant?
In general, boys are candidates for transplant if they have visible lesions on an MRI, but are showing no neurological symptoms, or at most early symptoms. Boys with an MRI Loes score less than 8 or 9 are usually considered suitable for transplantation.
How frequently should we have an MRI?
Ideally, your child should have an MRI every six months. If the child doesn’t yet have symptoms, and is undergoing treatment with Lorenzo’s oil, the regular MRIs will show whether there are any demyelinating lesions on the brain. Catching these lesions early significantly improves the chances of the other possible treatment—a bone marrow transplant—being successful. If your child already does have symptoms, it is important to monitor how fast the disease is progressing.
What is a Loes score?
The Loes score is a rating of the severity of abnormalities in the brain found on MRI. It ranges from 0 to 34, based on a point system derived from the location and extent of disease and the presence of atrophy in the brain, either localized to specific points or generally throughout the brain. A Loes score of 0.5 or less is classified as normal, while a Loes score of 14 or greater is considered severe.
It was developed by neuroradiologist Daniel J. Loes of the University of Minnesota, and is an important tool in assessing disease progression and the effectiveness of therapy. For example, even if your child shows no noticeable symptoms, if the Loes score deteriorates by more than one scale point with each six-month MRI exam, some specialists will recommend that you consider a stem cell transplant.
A pediatric neuroradiologist with ALD expertise is the best qualified healthcare provider to determine the Loes scale.
Should we and other family members be tested?
This is a difficult decision that only you can make, but there are important reasons why you and your family members should consider being tested for the ALD gene.
First, the only available treatments for ALD are treatments that work best during a short window of time—either before the onset of any signs of the disease, as with Lorenzo’s oil, or once abnormalities have appeared on brain MRI but before actual symptoms – or only minimal symptoms - have developed, as with stem cell transplantation. Genetic testing allows families to identify boys who carry the defective gene early in life, before the disease process begins. They can then pursue treatment with Lorenzo’s oil, and also monitor the child’s brain carefully with regular MRI scans so that they have the opportunity to pursue a transplant as early as possible once lesions begin to appear on the brain.
For women who may be carriers of the mutated gene, this information—along with good genetic counseling—can help them make decisions about planning their families. Knowledge of their carrier status can help women and their physicians better understand and manage the mild neurological symptoms that manifest in adulthood for some of these women.
Although transplantation is not currently recommended for men with adrenomyeloneuropathy, that may change as transplant technology becomes safer. Once this becomes the case, as with young boys, it will be very important to identify and closely monitor adult males with the mutated ALD gene, so that they may have the option to choose transplantation if MRI scans show brain lesions.
What is the prognosis and life expectancy for a child with ALD?
The onset of childhood cerebral ALD is usually between ages four and ten years. The prognosis is generally poor, particularly if the disease is not correctly diagnosed before significant symptoms develop. Many of these children die within one and ten years of the onset of symptoms. There are some treatment options (Lorenzo’s oil and stem cell transplants) that may alter this prognosis, but they are not guarantees.
How can a boy have ALD if his mother/aunt/grandmother is not a carrier?
A boy inherits the mutated ALD gene from his mother. However, it is possible for a boy to have ALD if his mother does not carry the mutated gene. This is because s an estimated 5%-7% of cases are de novo mutations, meaning that the gene mutation arose spontaneously in the child when it was not present in the mother.
I thought that ALD only affects boys. Is it rare/possible for young girls to be diagnosed with ALD?
The gene that causes ALD appears on the X chromosome; women are carriers of two X chromosomes, while men have one X and one Y chromosome. If a girl has one X chromosome with the ALD mutation, she can pass the disease along to her sons. She will not usually have the disease herself, but sometimes will show some mild symptoms, such as motor difficulties. This usually only appears in adult women.
Can Lorenzo’s Oil save our son?
If your son has been diagnosed with ALD because of a blood test, likely because another family member has been diagnosed with the disease or is known to be a carrier, he may benefit from Lorenzo’s oil. Treatment with Lorenzo’s oil is advisable only when the child has not yet shown any neurological symptoms, and has no visible lesions on the brain—in other words, he has the defective gene and will someday develop ALD or AMN, but has not done so yet.
How or where can we get Lorenzo’s Oil?
In the United States, Lorenzo’s oil is only available through prescription by physicians at the Kennedy Krieger Institute in Baltimore, which is studying the oil. You can contact the Institute about trial enrollment by calling +1 (443) 923-2750. Since it is not approved by the U.S. Food and Drug Administration, many insurers will not pay for it; Lorenzo’s oil costs upwards of $400 per month. Also, you can find out more information through the Myelin Project at www.myelin.org
Why shouldn’t we use Lorenzo’s Oil?w
Lorenzo’s oil does have side effects. It often can lead to thrombocytopenia, a condition in which there are not enough platelets—the cells that help blood to clot. This puts a child at risk of abnormal bleeding. Because it does not appear that Lorenzo’s oil is effective in treating children who have already begun to decline neurologically, it is not recommended that it be used in these patients because of the risk of the side effects.
What exactly is Lorenzo’s Oil?
Lorenzo’s oil is a combination of fats extracted from olive oil and rapeseed oil—specifically, a combination of the triglycerides of erucic acid and oleic acid in a 1:4 ratio. It is usually used in conjunction with a low-fat diet.
Is Lorenzo still alive?
Unfortunately, Lorenzo Odone passed away on May 30, 2008 -- one day after his 30th birthday. You can find more information on this wonderful person here.
What treatments are available for ALD?
What is the most effective treatment for ALD?
At present, there are only two treatments for ALD: Lorenzo’s oil and stem cell transplantation using either bone marrow stem cells or umbilical cord blood stem cells. These treatments appear to be most effective if they are used before the onset of symptoms.
Can you tell me more about transplants (bone marrow and cord blood)
There are currently two sources for transplanted stem cells: umbilical cord blood (UCBT) or bone marrow (BMT). In both cases, the goal is to provide the patient with healthy stem cells that produce a functioning ALD protein—the protein that is lacking in people with ALD.
Among the small number of patients who have had transplants, some have had their condition stabilize, and a few even made slight improvements. But there is a very narrow window in which stem cell transplantation appears to be effective—the time between when the brain lesions appear on an MRI, and when the boy experiences only mild clinical symptoms.
This treatment also has serious risks. Both types of transplantation require that the patient’s immune system essentially be wiped out by high-dose chemotherapy and/or radiation, so that their bodies do not reject the foreign donor cells. This leaves patients vulnerable to almost any kind of infection, and these procedures have a mortality rate that is as high as 40%.
The decision to pursue a bone marrow transplant is not an easy one and cannot be made lightly.
What is gene therapy and is it available now?
Gene therapy is a new approach to stem cell transplantation. Instead of finding a donor who is enough of a match to your child to donate bone marrow stem cells or umbilical cord blood stem cells, the transplant is done using the child’s own cells. The appropriate cells are removed from the patient with ALD, the correct genetic sequence is inserted into those cells, and they are then put back into the patient. The repaired cells will then produce the protein that had been missing or defective prior to treatment, and the disease process will halt or reverse.
This is a very promising area of treatment, but there are many scientific challenges to conquer and risks to be considered. At present, it is undergoing clinical trial in France and is not generally available.
How do we know if our boy is a candidate for transplant?
In general, boys are candidates for transplant if they have visible lesions on an MRI, but are showing limited or no neurological symptoms. Boys with an MRI Loes score of less than 8 or 9 are usually considered suitable for transplantation.
Are most transplants successful and are they dangerous?
Transplants are definitely dangerous. Because the body’s immune system must essentially be shut down by high-dose chemotherapy and/or radiation to prevent rejection of the “foreign” transplanted cells, the child is at risk from even the smallest cold or other infection. In addition, neurotoxic medications are needed to prevent Graft vs. Host Disease, in which infection-fighting cells from the donor recognize the patient’s body as foreign, and then it just as if they were attacking an infection. Statistics show that the mortality rate after such transplants can be as high as 40%. The disease also seems to briefly progress more rapidly after transplant—for about six months—meaning that the child will lose some additional brain function before improving, even if the transplant is successful.
However, for boys who are candidates for a transplant, it is currently the only option to halt the disease’s destruction of brain cells. Transplantation must be considered very carefully; there are no easy answers.
If our boy is not a candidate for a transplant, what other options exist?
Unfortunately, once the “transplant” window has closed, there are few other treatment options available. A preliminary study at University of Minnesota is demonstrating promising results in a small number of patients with advanced disease (please see “on the Horizon” section). Other treatments are palliative care—in other words, they cannot alter the course of the disease, but only make life as comfortable as possible for the patient and his family.
Can Lorenzo’s Oil be effective for treating ALD?
Recent studies indicate that Lorenzo’s oil may be effective in helping to prevent the onset of the disease’s symptoms in boys who have the genetic mutation that causes ALD. It is unclear, however, if Lorenzo’s oil can be effective as a treatment once symptoms have already begun to develop.
A man in our family has been diagnosed with AMN: What do we need to know? What do we do?
What treatment/medications are available for older men diagnosed with AMN?
It is important to treat the adrenal insufficiency (Addison’s disease) that generally accompanies AMN. Steroid drugs are used to replace the missing adrenal hormones, and must be taken for life.
Other approaches to managing the condition include physical therapy, specific treatments to manage urinary problems, and counseling. There are no known current treatments that change the course of AMN. Lorenzo’s oil has been tried in some patients, but results have been mixed. However, the Kennedy Krieger Institute and Johns Hopkins Hospital are now studying Lorenzo’s oil in adult men with AMN, and report some promise. You can find out more about the trial from The Adrenoleukodystrophy Foundation.
Can a man with AMN/ALD safely have children who are free from the disease?
It depends. A man with AMN/ALD does not pass along the mutated gene to his sons, so his sons will be free of the disease. All of his daughters, however, will carry the mutation.
What is the prognosis and life expectancy of a man with AMN?
It depends on the type of AMN that he has. In some people, AMN affects the spinal cord only, while in others, it affects both the spinal cord and the brain. About 54% of patients with AMN have normal brain function, while the other 46% have some type of brain involvement. Magnetic resonance imaging (MRI) can determine if the brain is affected by the disease.
Patients without cerebral involvement have a significantly better prognosis than those in whom the brain is affected. They will have motor difficulties due to the disease’s effects on their spinal cord, but they can generally maintain successful lives and have a reasonably normal life expectancy. In this case, their condition can usually be effectively cared for with physical therapy, management of urinary control problems, and counseling.
AMN with cerebral involvement has a generally poorer prognosis. Some patients with AMN—approximately one in five—have severely progressive brain involvement, marked by cognitive decline and behavioral problems. This form of AMN can be completely disabling and even fatal.
Symptoms of AMN generally appear in the late 20s, but onset can occur anywhere from the teens to as late as the fifties.
How can a man have AMN if his mother/aunt/grandmother is not a carrier?
In some unusual cases—about 5% to 7% of all cases, according to research published by the late Hugo Moser, M.D., a pioneer in ALD studies—ALD arises from “de novo” mutations—genetic mutations that were not present in the parents.
How effective is Riluzole (also called Rilutek) in treating AMN?
Riluzole is a drug approved to treat amyotrophic lateral sclerosis (ALS). Patrick Aubourg, a professor of pediatrics at Hospital Saint-Vincent de Paul in Paris, has been studying Riluzole to see if it has any effectiveness in treating AMN.
Who is David Cry and how can he help?
David Cry is the founder and chief executive officer of The Adrenoleukodystrophy (ALD) Foundation. He first began having symptoms of adrenomyeloneuropathy in the fall of 1997. Since that time, David has overcome tremendous obstacles in order to assist with the development of novel therapies that will combat the effects of both ALD and AMN. He is a great source of knowledge for AMN patients.
Female carriers of ALD/AMN: What do we need to know?
Are there any symptoms for women to be aware of for carriers of ALD/AMN?
Yes. Although women who carry the ALD gene mutation do not develop the brain disease, some display mild symptoms of the disorder. These symptoms usually develop after age 35, and primarily include progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, and urinary problems.
Can a woman carrier of ALD/AMN have children who are free from the disease?
Yes. With each conception, there is a 50-50 chance of passing on the defect on the X chromosome. If the defect is passed on, a female child will be a carrier, and a male child will have the disease. Prenatal testing can identify, during pregnancy. whether the defective gene has been passed on.
Can a man have ALD/AMN if his mother/aunt/grandmother is not a carrier?
In rare cases, yes. About 5% to 7% of ALD/AMN cases arise from “de novo” genetic mutations—mutations that were not present in the child’s parents.
Is there treatment for women carriers?
Other than symptom management, there is no specific treatment at present. A trial at the Kennedy-Krieger Institute in Baltimore is now investigating whether Lorenzo’s oil has any benefit for adult men with AMN, and women who are carriers and have symptoms.
How does a woman know if she is a carrier?
A simple genetic test can identify carriers of the ALD/AMN gene with 99% accuracy. The test requires only a blood sample.
Should other people in our family be tested?
Yes. Testing for ALD can be stressful, but finding out whether a woman is an ALD carrier or a boy or man has the disease is essential. It helps families pursue treatment as early as possible for boys with the disease gene, and women who are carriers plan their families.
Family testing and planning: What can we do? What do we need to know?
How can a woman find out if she is a carrier of ALD/AMN?
A screening test can identify carriers of the ALD/AMN gene with 99% accuracy. The test requires only a blood sample. Please contact Kennedy Krieger for more information on having the blood test.
If any person in the family has ALD, AMN, or is a carrier, who else in the family should be tested?
It depends on their relationship to the person who has ALD. For example, if a boy has ALD, his mother should be tested for the mutation, as should all of his siblings. His mother’s siblings—especially sisters—should be tested as well, since they may also have inherited the ALD mutation and be at risk for passing it on to their children. Genetic counselors can best advise you as to who in your family should be tested.
Can we test an unborn child in utero?
Yes. Prenatal testing can be done using either chorionic villus sampling (CVS) or amniocentesis (see 6.4).
How can a person (male/female) make certain any future children are born free from ALD/AMN?
A man who has ALD or AMN will not pass the disease gene to any sons, but all of his daughters will carry the mutation. A woman who carries the mutated gene has a 50-50 chance of transmitting the mutation in each pregnancy.
To avoid passing along the gene, there are two options: in vitro fertilization with preimplantation genetic diagnosis, which would avoid implanting embryos with ALD. The other option is prenatal testing using either chorionic villus sampling or amniocentesis, which is performed early in pregnancy
Prenatal testing to determine whether an unborn child is affected is possible if a specific ALD mutation has been identified in a family. There are two tests that can be used: chorionic villus sampling, done at 10-12 weeks’ gestation by removing a tiny piece of the placenta and examining the cells; or amniocentesis, done after 14 weeks’ gestation by removing a small amount of amniotic fluid and analyzing the cells in the fluid. Both procedures carry with them a small risk of miscarriage, so it is important to discuss options with a genetic counselor before proceeding.
What is genetic counseling?
Professional genetic counselors explain the process by which diseases are passed along genetically, and help families understand their risk of transmitting genetic disorders to their children. They counsel families about options for finding out their genetic disease risk, and provide information that will help them make decisions about pursuing genetic testing and what to do with the results of those tests.
What is IVF PGD?
IVF PGD is in vitro fertilization pre-implantation genetic diagnosis. It analyzes expendable cells from days-old embryos that have been fertilized in vitro, allowing parents undergoing IVF to determine which, if any, embryos are affected by ALD and choose healthy embryos for implantation. This is only possible for families in which a mutation in the ALD gene has already been identified.
What research is taking place on ALD and AMN?
Stem cell transplants – bone marrow and cord blood
Scientists are studying ways to make stem cell transplants safer and beneficial for more patients.
One group at the University of Minnesota has used a combination of stem cell transplantation and therapy with a drug called Mucomyst, approved by the FDA to treat cystic fibrosis and acetaminophen overdose. This was tried on three boys whose disease had already progressed past the point when bone marrow transplant is generally thought to be effective. So far, MRI scans show no further progression of the disease, and the approach is being tried in additional patients. (Bone Marrow Transplantation (2007) 39, 211–215. doi:10.1038/sj.bmt.1705571)
Gene therapy is a new approach to stem cell transplantation. Instead of finding a donor who is enough of a match to your child to donate bone marrow stem cells or umbilical cord blood stem cells, the transplant is done using the child’s own cells. The appropriate cells are removed from the people with ALD, the correct genetic sequence is inserted into those cells, and they are put back into the patient The repaired cells will then produce the protein that had been missing or defective prior to treatment, and once successfully engrafted, the disease process will halt or reverse.
This is a very promising area of treatment, but there are many scientific challenges to conquer and risks to be considered. At present, it is undergoing clinical trial in France, with a very small group of patients, and is not generally available.
This is being investigated at University of Minnesota.
The Kennedy Krieger Institute is studying Lorenzo’s oil as a treatment for asymptomatic boys with ALD, ages 18 months to six years. To find out if your son is eligible to enroll in the trial, contact Kennedy Krieger at 800-873-3377.
There is one U.S. clinical trial of treatment for ALD currently ongoing. The Kennedy Krieger Institute is studying Lorenzo’s oil as a treatment for asymptomatic boys with ALD, ages 18 months to six years. To find out if your son is eligible to enroll in the trial, contact Kennedy Krieger at 800-873-3377.
What is The Stop ALD Foundation doing?
Find information on our current project here.
How can I help?
How can I make a donation to The Stop ALD Foundation?
There are many options for making donations to the Stop ALD Foundation. You can donate by check, credit card, or wire transfer; you can also donate appreciated stock or other assets. In addition, if your company has a charitable matching program, you may be able to double the value of your gift.
There are currently only two available treatments for childhood cerebral ALD: Lorenzo’s oil and stem cell transplantation, using either umbilical cord stem cells or bone marrow stem cells. Both treatment approaches have shown promise, and been effective for some boys with ALD, but they also both have drawbacks. While research indicates that these treatments may be able to arrest the progress of the disease, neither can dramatically repair the damage done by ALD once it has already begun. To do that, a treatment would have to actually restore the lost myelin.
Both Lorenzo’s oil and stem cell transplantation are considered treatments only for boys with childhood cerebral ALD; the options for treating men with adrenomyeloneuropathy (AMN), the adult form of the disease, are more limited. Currently, doctors will not perform stem cell transplantation on adults with the disease, generally because the risks of the treatment are considered to outweigh the potential benefits. But as transplantation technology improves and becomes safer, it is possible that stem cell transplantation will be available for men with AMN.
Learn more about...
Stem Cell Transplantation
Lorenzo’s oil is a combination of two fats extracted from olive oil and rapeseed oil. It was developed by Augusto and Michaela Odone to treat their son, Lorenzo, after he was diagnosed with ALD in 1982. The mixture of fatty acids in Lorenzo’s oil works to reduce the levels of very long chain fatty acids, which are known to cause ALD.
Recent studies indicate that Lorenzo’s oil may be effective in staving off the onset of symptoms in boys with the disease who have not yet become symptomatic. A study published in the Archives of Neurology in July 2005 followed 89 boys with ALD who took Lorenzo’s oil and ate a low-fat diet. The boys had normal MRIs and no symptoms of ALD, but had been screened for the disease because they had an affected relative. After an average follow-up of seven years, 74% of the boys still had normal MRIs and no neurological symptoms.
This study does not definitively prove that Lorenzo’s oil is what kept the boys from developing symptoms. It is possible that the boys who did not develop symptoms would not have developed the disease in childhood anyway, and they all could still develop adrenomyeloneuropathy (the later-onset form of the disease) when they reach adulthood.
Nonetheless, the study’s results are encouraging. Parents with a child who may be at risk for ALD can inquire about enrolling in a clinical trial at the Kennedy Krieger Institute, 800-873-3377. That is presently the only way to obtain Lorenzo’s oil in the U.S. Since it is not approved by the Food and Drug Administration and still considered an experimental drug, not all insurance companies will provide coverage for the oil, which costs over $400 for a month’s treatment.
Stem Cell Transplantation
Boys with ALD who have a Loes score lower than 8 or 9 (an MRI measure of the severity of the disease) are generally considered candidates for stem cell transplantation. There are currently two sources for transplanted stem cells: umbilical cord blood (UCBT) or bone marrow (BMT). In both cases, the goal is to provide the patient with healthy stem cells that produce a functioning ALD protein—the protein that is lacking in people with ALD. Scientists believe that this works as some portion of the donated cells, which are not genetically defective, find their way into the brain, express the missing or nonfunctioning ALD protein, and halt or even reverse the brain damage.
Although much of this theory remains to be scientifically proven, these transplants have been successful; among the small number of patients who have had transplants, some have had their condition stabilize, and a few even made slight improvements. But there is a very narrow window in which stem cell transplantation appears to be effective—the time between when the brain lesions appear on an MRI, and when the boy first starts showing symptoms.
This treatment also has serious risks. Both types of transplantation require that the patient’s immune system essentially be wiped out by high-dose chemotherapy and/or radiation, so that their bodies do not reject the foreign donor cells. This leaves patients vulnerable to almost any kind of infection, and these procedures have a mortality rate that is as high as 40%. It can also be difficult to find a well-matched donor, and sometimes the donor cell graft does not “take.”
Unfortunately, there also appears to be a period of about six to eighteen months following transplant when the disease progression continues. This means that, even in a best case scenario, the child emerging from this medical procedure will have more advanced brain damage than he had going in. If the downward slide is then arrested by the transplant, this may be a trade-off worth making. But in boys suffering from a late diagnosis, often a BMT will only rapidly advance their condition into a completely vegetative state.
Clearly, the decision to pursue a bone marrow transplant is not an easy one and cannot be made lightly.
It is essential to diagnose ALD as early as possible. All the evidence indicates that the two currently available treatments for the disease—Lorenzo’s oil and stem cell transplantation—only work during a very narrow window either before symptoms develop, or very early after their onset. Once the disease has progressed and symptoms have become severe, there are currently no treatments that can replace the lost myelin and the only treatments available are palliative.
Unfortunately, cases of ALD are often missed or misdiagnosed during the critical period of early onset. This is often because diagnosing ALD can be a tremendous challenge for many physicians. The earliest symptoms of the disorder in childhood can easily be mistaken for a number of other, much milder and much more common developmental and behavioral problems, such as attention deficit disorder (ADD/ADHD) or learning disabilities.
Learn more about...
What Should Parents and Families Look For?
What Should Physicians Look For?
What Should Parents and Families Look For?
It is very difficult to differentiate ALD from other conditions, such as ADHD, epilepsy, autism, and other learning disabilities, particularly if you are not aware that a genetic predisposition to the disease runs in your family. However, if you notice some of the following things, be sure that your child’s physician is considering the possibility of ALD—especially if you have a family history of neurological problems:
Late-onset ADHD or other attention problems.
A child with ADHD usually shows attention problems in preschool or early school years, while ALD symptoms appear between ages six and 10. If your son had no trouble paying attention in kindergarten but is suddenly developing problems in second grade, mention this to your doctor.
Lack of response to medications for ADHD.
If your child has been receiving a stimulant medication for ADHD and has not responded, your doctor will probably suggest a change of dose or change of medication. Ask for a blood test for ALD and a brain MRI at the same time.
If your doctor diagnoses your child with Addison’s disease, a test for ALD should be automatic, since ALD is the most common reason for Addison’s disease in childhood.
Problems with vision.
Visual impairment, caused by lesions on the optic tract, is characteristic of early seen ALD, and is frequently misdiagnosed.
What Should Physicians Look For?
Some key clues that should alert physicians to consider the possibility of ALD include:
A family history of significant medical conditions, early morbidity, or symptoms of behavioral or developmental disorders that appear to be genetic;
Signs of abnormal development in the child;
Changes in the child’s functioning, such as declines in cognition, learning, behavior, or emotional regulation;
Rapid acceleration of such changes;
Late onset of symptoms that typically occur earlier in childhood, such as attention or learning problems;
Visual-spatial or visual-perceptual difficulties; and
Lack of sustained response to symptomatic therapies.
Physicians may consider referring to the following table when ALD is included as a differential diagnosis:
Developmental/Behavioral Disorders (e.g., ADHD)
Sibling with unexplained death or neurologic abnormality (such as multiple sclerosis); Addison’s disease; or alternatively, lack of a suggestive family history
Learning disabilities, attention disorders, behavior problems often reported in family members
Onset or marked worsening of symptoms; preschool and early years often normal
Behavioral/developmental symptoms chronic, often noticed when child begins school; ADHD diagnosis requires onset of symptoms before age 7
Symptoms of multiple externalizing and internalizing disorders (i.e. depression or anxiety) common; neurological signs such as seizures often present; adrenal insufficiency often present
Symptoms of multiple externalizing and internalizing disorders (i.e., depression or anxiety) are less common; adrenal insufficiency not usually found
Adapted from Ievers CE, Brwon RT, McCandles SE et al. J Dev Behavior Pediatrics. 1999;20(1):31-35.
Read the MediView Report, Avoiding the Misdiagnosis of Adrenoleukodystrophy: Distinguishing ALD from ADD/ADHD.
Once ALD is suspected, there are two tests that must be done: a blood test and a brain scan. The blood test analyzes the amount of very long chain fatty acids, which are elevated in ALD. This test has the highest degree of accuracy in males; however, it can sometimes miss the presence of the mutated gene in women who are carriers of the disease.
If the blood test suggests ALD, a magnetic resonance imaging scan (MRI) will be performed to determine if the disease has begun to do damage to the brain. Lesions on the brain caused by the destruction of the myelin will appear on MRI before any neurological or psychological symptoms appear. The MRI scan will produce something called a Loes score, which rates the severity of the damage to the brain on a scale from 0 to 34. A score of 0.5 or less is normal; a score of 14 or more indicates severe ALD.
When a child is diagnosed with ALD, among the first questions many families ask are “Are our other children at risk?” or “Can we safely have more children?” Genetic testing is the only way to answer that question. DNA-based blood tests can accurately identify both women who are carriers of the gene, and boys and young men who have ALD and may not yet be showing symptoms.
Research shows that screening not just the parents and siblings of boys with ALD, but extended family members as well, is the best way to detect the disease at a time when treatment can be beneficial.
Although it is not currently feasible to screen all pregnant women for the ALD mutation, prenatal tests and genetic counseling are available to help families plan their pregnancies and avoid passing the ALD gene on to their children.
Amniocentesis and chorionic villus sampling (CVS) can both detect the ALD abnormality, but only if testing laboratory or physician is specifically looking for it.
Doctors can contact the Kennedy Krieger Institute to request genetic testing.
AdrenoleukodystrophyAdrenoleukodystrophy, or ALD, is an x-linked metabolic disorder, characterized by progressive neurologic deterioration due to demyelination of the cerebral white matter. Brain function declines as the protective myelin sheath is gradually stripped from the brain’s nerve cells. Without that sheath, the neurons cannot conduct action potentials—in other words, they stop telling the muscles and other elements of the central nervous system what to do.
This sequence of events appears to be related to an abnormal accumulation of saturated very-long-chain fatty acids (VLCFA) in the serum and tissues of the central nervous system, which sets off an abnormal immune response that leads to demyelination. It is unclear exactly how this chain of events works, but scientists do know that it has its roots in genetics.
ALD is caused by a genetic abnormality, commonly referred to as a “genetic mutation”, affecting the X chromosome, otherwise known as an “x-linked” condition. Everyone has two sex chromosomes: women have two X chromosomes and men have an X and a Y chromosome. If a woman inherits the abnormal X chromosome, she still has a normal, second X chromosome to help balance out the affects of the mutation. Boys and men do not have a second X chromosome, so if they inherit this genetic abnormality, they will get the disease.
ALD takes several forms, which can vary widely in their severity and progression. They include:
Childhood cerebral demyelinating ALD. This is the most common form of ALD, representing about 45% of all ALD cases. It is characterized by an inflammatory process that destroys the myelin, causing relentless progressive deterioration to a vegetative state or death, usually within five years.
Adrenomyeloneuropathy. The majority of other cases of the disease occur as the adult form, known as AMN. In about half of the sons who inherit the mutated ALD gene, symptoms of the disease do not develop until young adulthood, and in general, they progress more slowly. Beginning in their 20s and 30s, these young men exhibit neurological based motor lesions in their extremities. These lesions progress over many years and are inevitably accompanied by moderate to severe handicap. In approximately one third of these patients the central nervous system also becomes involved. These young men undergo the same mental and physical deterioration as the previously described boys. The progress of the disease is slower, usually declining to a vegetative state and/or death in 5 years or longer. There is no effective treatment for the adult onset of ALD, which is commonly referred to as adrenomyeloneuropathy (AMN); rather, medication and therapies are employed in a palliative manner.
Addison’s disease. (Hypoadrenocorticism) Most boys and men with ALD/AMN have Addison’s disease, a disorder of the adrenal gland; in about 10% of ALD cases, this is the only clinical sign of the disorder. The adrenal glands produce a variety of hormones that control levels of sugar, sodium, and potassium in the body, and help it respond to stress. In Addison’s disease, the body produces insufficient levels of the adrenal hormone, which can be life-threatening. Fortunately, this aspect of ALD is easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness)
Female ALD. Although women who carry the ALD gene mutation do not generally develop the brain disease itself, some display mild symptoms of the disorder. These symptoms usually develop after age 35, and primarily include progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, and urinary problems.