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.