Adrenoleukodystrophy

Stem cell transplants (HSCT) are not offered before a boy exhibits early signs of X-linked adrenoleukodystrophy because stem cell transplants are not without their own risks. The stem cell transplant itself can have a mortality rate of 20-40%. Because of the variation in the degree of severity of symptoms it is recommended that boys do not undergo bone marrow transplant until cerebral (brain) findings are identified. Even at this point deciding to pursue a transplant is still a personal family choice.

Who you inform about your child’s diagnosis is completely up to you. At minimum, your child’s healthcare team needs to know about their diagnosis. In addition, many families benefit from informing and educating family members as well as it helps build up their support system.

Further testing should start with the mother of a boy with X-linked adrenoleukodystrophy, or both parents of a daughter thought to be a carrier. Based on parental status, the need to test siblings or other relatives can be established. A woman who is a carrier may want to inform her sisters or female cousins in particular. A genetic counselor, geneticist, or other physician can look at your family tree to help determine which relatives would be good candidates for testing and the best order to test these relatives. To find a genetic counselor near you who can discuss t genetic testing, visit the National Society of Genetic Counselors Find a Genetic Counselor website.

Many support group websites offer stories of families affected by adrenoleukodystrophy. The ALD Life organization offers many patient stories in their ALD Diaries. The 1992 film Lorenzo’s Oil depicts the story of one family whose son, Lorenzo Odone, was diagnosed with X-linked adrenoleukodystrophy.

The organ and body systems most commonly affected in X-linked adrenoleukodystrophy are the adrenal glands, the brain and nervous system, and the genitourinary system. Changes to these systems may include a decrease in certain hormones, behavior changes, problems with coordination, and sexual dysfunction. Symptoms and the severity of those symptoms vary between affected individuals.

Specialist doctors for patients with adrenoleukodystrophy will depend on the individual patient’s symptoms. Some specialists a patient might see include an endocrinologist (hormone doctor), neurologist, physical therapist, psychologist, geneticist, and/or a urologist.

Finding a genetic counselor and/or a medical geneticist near you would be an ideal way to make sure you have the information you need for your adrenoleukodystrophy to be managed correctly. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.

Make sure your primary care physician has the appropriate information on adrenoleukodystrophy in order to ensure that you are receiving the proper medical management.

Management for the adrenomyeloneuropathy form of adrenoleukodystrophy is typically symptomatic. This can involve physical therapy, management of urinary symptoms, and family or job counseling.

Adrenoleukodystrophy can be abbrievated ALD or X-ALD, for X-linked adrenoleukodystrophy.

Children with adrenoleukodystrophy usually begin to show symptoms between 4 and 10 years of age. If left untreated, the prognosis can be poor. Children who are not treated or there is a significant delay in diagnosis (allowing significant symptoms to develop) die within one to ten years after symptoms develop. Available treatment options have been shown to alter prognosis, but it is not a guarantee. For people who develop symptoms later on, disease progression and prognosis vary widely from person to person.

Preimplantation genetic testing (PGT) is a way that embryos can be tested for a familial genetic condition before they are implanted. It can be done for adrenoleukodystrophy if the specific genetic change in the family has been identified. After eggs are fertilized using in vitro fertilization, one or more cells are taken from the embryo and genetic testing is performed to look for the change in ABCD1. Then embryos that do not have the change are specifically chosen to be implanted for the pregnancy.

Adrenoleukodystrophy is a genetic condition that primarily affects males and leads to problems with the adrenal glands and the nervous system. The adrenal glands function to produce hormones and are located above the kidneys. There are multiple forms of X-linked adrenoleukodystrophy that can be divided based on the symptoms that are present in any one particular patient. Childhood cerebral forms have an onset of ages 4-8 and symptoms include attention problems, poor school performance, difficulty in understanding speech, reading comprehension problems, clumsiness, and problems with eyesight. Children with this form may also have seizures and problems progress over time. The adrenomyeloneuropathy (AMN) form has symptoms often beginning in 20s-40s and symptoms include leg weakness, difficulties with digestion and sexual dysfunction that gets worse with time. Individuals with the Addison-disease-only type typically start showing symptoms in childhood that may include vomiting, weakness and changes in skin coloring. These problems can be helped with hormone replacement therapy.

The first symptoms noticed by an individual with adrenoleukodystrophy will vary depending on what type of the disorder they have. In the childhood cerebral type, often early symptoms appear similar to ADD and many boys are first evaluated due to problems in school.

In the adrenomyeloneuropathy type, the first symptoms are often numbness or tingling in the feet and legs and stiffness or weakness in the feet and legs that can cause difficulty walking. Changes in bowel control and sexual function are also seen in this type.

In the Addison-disease-only type, the first symptoms are related to the adrenal glands not working properly. These symptoms include unexplained vomitting, weakness, or even coma. This type can present in childhood or adulthood, but often presents by 7.5 years of age.

The normal function of the ABCD1 gene is to produce a protein called the adrenoleukodystrophy protein (ALDP). When the ABCD1 gene is changed in someone with adrenoleukodystrophy, it results in a lack of the adrenoleukodystrophy protein. The role of this protein in our bodies is to bring specific fatty acids called very long chain fatty acids, or VLCFAs, into the peroxisomes, where they will be broken down. Peroxisomes are small sacs in our cells that help process many different molecules, including very long chain fatty acids. Without sufficient adrenoleukodystrophy protein, these fatty acids build up in the body, becoming toxic. Research shows that the high levels of very long chain fatty acids causes the breakdown of the insulation on our nerve cells, the myelin.

Adrenoleukodystrophy is caused by changes in the ABCD1 gene, located on the X chromosome.

If a person inherits a "variant of uncertain significance" in the gene associated with adrenoleukodystrophy, ABCD1, this means that we see a change in the gene, but we are unsure if the change will actually have an effect on the person. Further research will be needed to see if a genetic change is disease-causing or if it is benign. If a person learns they have a variant of uncertain significance, their diagnosis and medical management would be based on symptoms and blood testing for very long chain fatty acids in the blood.

Only women can be carriers of adrenoleukodystrophy. Carriers of X-linked adrenoleukodystrophy have a change in one of their ABCD1 genes but also have another copy that is functioning properly. Females can be carriers because they have two copies of the X chromosome and therefore two copies of ABCD1. Most women who are carriers do not show signs and symptoms of the condition, but an estimated 20% of carrier females will show moderate paraparesis (difficulty using the lower limbs), usually in middle age or later life.

Males cannot be carriers because they only have one X chromosome. Therefore, if a male has a change to ABCD1, he has no normally functioning copy of that gene, and will express adrenoleukodystrophy in some way.

Males have one X and one Y chromosome. All the daughters of a male with X-linked adrenoleukodystrophy will inherit the ABCD1 gene that isn’t working properly because that is the only X chromosome a male has to pass on. That daughter would most likely inherit a normally functioning ABCD1 gene from her mother, and therefore she would be a carrier. Most carriers do not show symptoms of the condition. If they do show symptoms, these symptoms are less severe than those of a male. Sons of a male with X-linked adrenoleukodystrophy will have no risk of inheriting the condition, because they do not receive their father’s X chromosome, only his Y chromosome.

The main symptoms of X-linked adrenoleukodystrophy depend on the specific form an individual has.

In the childhood cerebral form, early symptoms typically include difficulties in school and with paying attention. Symptoms can then progress to more serious attentional problems, reading problems, deterioration of handwriting skills, problems with spatial orientation, behavior problems, and difficulty with balance. Seizures are also not uncommon. Individuals with this form also have improperly functioning adrenal glands. These glands are located above the kidneys and produce different hormones. These symptoms usually begin between ages 4 and 8. After symptoms begin they can progress very quickly over the course of 6 months to 2 years.

In cases of adrenomyeloneuropathy (abbreviated AMN) symptoms typically begin as muscle stiffness or weakness and difficulty with bowel movements or sexual dysfunction. Problems with the adrenal system or cognitive problems can also be present. This type also manifests later than the childhood cerebral type, usually in the individual’s twenties.

In cases of Addison-disease-only type, the main symptoms are related to adrenal problems which can cause vomiting, weakness, or even coma. Other common symptoms of Addison-disease-only type are low blood pressure, abdominal pain and darker areas of skin color or pigmentation. Some degree of neurological disability may present later, usually with similar symptoms to AMN. The Addison-disease-only type normally presents around 7.5 years of age, but can present anytime from age 2 until adulthood.

In more rare cases, main symptoms can be headache, behavioral problems, memory loss, clumsiness, or bladder or bowel dysfunction.

The following evaluations are recommended after an individual is diagnosed with adrenoleukodystrophy:

Resources to teach others more about adrenoleukodystrophy include:

Hematopoietic stem cell transplantation has not been proven to be useful in children with advanced stage adrenoleukodystrophy. If your child is in the advanced stages of adrenoleukodystrophy, the benefits of the procedure do not outweigh the risks. Your child would not be a candidate because the hematopoietic stem cell transplantation cannot reverse damage to the neurological system. Children who are candidates for this procedure are children who are newly diagnosed and do not have advanced stage cerebral disease.

Variable expressivity refers to the types of symptoms a disorder presents with, and if there is variation from one person with the disease to another. There is definitely variable expressivity in adrenoleukodystrophy, as people with the same changes to their ABCD1 gene can have very different symptoms. Even within the same family, different individuals may present with different forms of the disease.

Penetrance refers to whether all people with the genetic change will have the disease or not. Although there is a great deal of variable expressivity in adrenoleukodystrophy, 100% of males with a disease-causing ABCD1 mutation will have elevated levels of very long chain fatty acids in their blood. Additionally, although some males may appear to be asymptomatic, nearly all affected males will show neurological symptoms by adulthood.

A genetic counselor can provide you with more information about Tyrosinemia Type I. Genetic counselors are healthcare professionals that have specialized training in medical genetics and counseling to provide personalized help to patients on their genetic health. Genetic counselors can be found on the National Society of Genetic Counselors website.

While no single symptom is characteristic of X-linked adrenoleukodystrophy, certain combinations of symptoms can prompt further evaluation. For example, young boys showing signs of attention deficit disorder (ADD) and also problems with memory, abnormal behaviors, vision loss, and/or worsening clumsiness may need additional testing. Men in their 20s-30s with worsening muscle stiffness and problems with bowel control or sexual function should consider evaluation for adrenomyeloneuropathy. In addition, males who have adrenocortical insufficiency or are diagnosed with Addison’s disease without an identified cause should consider further workup.

Medical evaluations are the best tools to recognize X-linked adrenoleukodystrophy. If the cerebral form is present MRI findings can be very characteristic. Blood testing that shows an abnormally high amount of very long chain fatty acids is also a sign of X-linked adrenoleukodystrophy.

Some states, including New York, California, Minnesota, and Connecticut test for X-linked adrenoleukodystrophy (ADL) at birth. Other states are in the process of adding ADL to their testing panel. In February 2016, Secretary of the Department of Health & Human Services, Sylvia Burwell, approved the addition of adrenoleukodystrophy to the federal government’s list of diseases recommended for state newborn screening programs, the Recommended Uniform Screening Panel (RUSP). This may lead many other states to include adrenoleukodystrophy in their newborn screening programs. Advocating for newborn screening is the goal of many support groups, such as the Myelin Project. To find out which disorders your state’s newborn screening looks for, please visit Baby’s First Test. This website can provide you with a link to your state’s newborn screening website.

If you have reason to believe your infant is at risk for adrenoleukodystrophy, speak to your physician about whether newborn testing would be helpful or how that could be arranged.

There are two main types of testing to diagnose adrenoleukodystrophy: measuring very long chain fatty acids and DNA testing of the ABCD1 gene. Looking for the very long chain fatty acids in the blood should be sufficient to determine a diagnosis of adrenoleukodystrophy in most cases. If there is question, genetic testing of the ABCD1 gene can be performed. DNA testing of ABCD1 can also be useful for carrier testing, testing other family members, or prenatal testing. A genetic counselor can help you discuss and obtain genetic testing. Genetic counselors can be found on the National Society of Genetic Counselors website.

There are many clinical studies going on to study possible treatments for X-linked adrenoleukodystrophy. Please see: Clinical Trials.gov for a listing of clinical trials and The Starbeam Study for information about a clinical trial investigating gene therapy as a treatment for adrenoleukodystrophy. Many support groups, such as ALD Connect, also contain information about ongoing research and clinical trials.

There are treatments available for X-linked adrenoleukodystrophy. Specific treatments depend on what symptoms are being exhibited. If the adrenal glands are not functioning well, corticosteroids will be supplemented. This is essential and can be life-saving. This will be monitored by an endocrinologist (doctor who specializes in hormones).

Physical therapy can be used for patients who have difficulty walking, such as those with the adenomyeloneuropathy type of adrenoleukodystrophy.

In boys who exhibit early signs of brain changes hematopoietic stem cell transplant (HSCT) or bone marrow transplant might be an option. This therapy is for boys who show very early signs of neurological involvement on MRI, but who don’t have extensive neurological impairment, and have a normal clinical neurological exam. HSCT has risks of its own, with a morbidity and mortality rate (the risk of death or serious illness) of 20%. Finding a suitable donor can also be challenging. In boys with do undergo stem cell or bone marrow transplant, only 30-35% of them will go on to develop childhood cerebral disease.

Lorenzo’s Oil is an investigational treatment for boys with adrenoleukodystrophy. This oil, a mix of erucic and oleic acids, along with a low-fat diet, is used to reduce the very long chain fatty acids that accumulate in adrenoleukodystrophy. This therapy has showed promise in the prevention of the cerebral childhood manifestation, but it is not approved by the FDA and is still considered investigational. To find a metabolic dietitian specializing in diets for people with metabolic conditions and who can discuss with you options for getting Lorenzo’s oil, visit the GMDI Find a Metabolic Dietitian webpage.

Other potential treatments, such as gene therapy, are currently undergoing clinical trials.

ABCD1 is not a predisposition gene. Mutations in this gene are considered causative of X-linked adrenoleukodystrophy. It is not possible to predict which symptoms a male will show, nor is it possible to know in advance which female carriers will demonstrate some symptoms. In May 2019 a small study of individuals with childhood-onset X-linked adrenoleukodystrophy who also have a genetic variant called APOE4 may be at increased risk for more severe disease. However, this study requires further follow-up to determine if APOE4 is in fact adversely affecting the severity of X-linked adrenoleukodystrophy.

Before symptoms are evident for adrenoleukodystrophy, surveillance is very important. This can include brain MRIs to assess for cerebral (brain) changes and function of the adrenal gland. Dysfunction of the adrenal gland can be life-threatening.

There are multiple options for a woman who is a carrier for X-linked adrenoleukodystrophy to expand her family. These options are deeply personal and there is no one "right" way to go about building a family. Options include using preimplantation genetic diagnosis and in vitro fertilization to ensure the child will not have X-linked adrenoleukodystrophy, having a natural pregnancy and doing prenatal testing, having a natural pregnancy and testing for X-linked adrenoleukodystrophy at birth, using a donor egg to conceive, and/or choosing to adopt additional children. Some of these options, such as preimplantation genetic diagnosis and some forms of prenatal testing, require that the specific genetic change in ABCD1 be identified. The best time to discuss your options for family-building is prior to pregnancy. A genetic counselor can help explain each of these options in more detail and help you evaluate which option is best for you. The genetic counselor will not tell you which option you should pursue. Genetic counselors can be found on the National Society of Genetic Counselors website.

Children of a woman who is a carrier of adrenoleukodystrophy each have a 50% (1/2) chance of inheriting the same change. If the child is a male, he would be expected to show symptoms. The specific sub-type of adrenoleukodystrophy he fits into may vary. If the child is a female, we would expect that she would be a carrier for the condition (like her mother) and show no symptoms or much less severe symptoms.

No immediate interventions are required if a baby is diagnosed with X-linked adrenoleukodystrophy after birth. Screening of the baby’s hormone levels and monitoring brain MRIs will begin at about 18 months to look for any early signs or symptoms.

Below are a few helpful steps if you have been diagnosed with ALD and want to know who to see and what to do next:

If the child is not having symptoms of adrenoleukodystrophy, screening is recommended every 6-12 months so that the disease can be recognized at the earliest possible signs. This screening includes both MRI and monitoring adrenal function.

X-linked adrenoleukodystrophy is inherited from a parent approximately 95% of the time. In the remaining 4-5% of cases, there is a new mutation, or genetic change, in the ABCD1 gene of the affected patient. A new genetic change is also called a de novo change or mutation.

X-linked adrenoleukodystrophy is inherited in an X-linked manner, because the ABCD1 gene is located on the X chromosome. Women who are carriers for X-linked adrenoleukodystrophy have a 50% chance of passing the changed ABCD1 gene to each of their children. If a daughter inherits the change, she too will be a carrier, or mildly affected. If a son inherits the change he will likely exhibit full symptoms of X-linked adrenoleukodystrophy. Men who have X-linked adrenoleukodystrophy will not pass their genetic change on to any of their sons, but all of their daughters will be carriers.

There are many existing support groups that you can participate in. Additionally, ALD support has opportunities to participate in online Forums or groups. You can join an already formed group or form your own with people you meet. Please see: http://adrenoleukodystrophysupport.org/.

Many of the support groups offer money to help with research. For example some of the funds from The Myelin Project and the United Leukodystrophy Foundation go to support scientific research.

The first diagnostic test for adrenoleukodystrophy is measuring very long chain fatty acids (VLCFA) in the blood. This is typically diagnostic for the condition. DNA testing of the ABCD1 gene may also be used to identify the genetic change in the individual. Testing is available at several different labs in the United States. A list of these labs can be found at the Genetic Testing Registry.

[link url="www.Clinicaltrials.gov” target=”_blank”>Clinicaltrials.gov has many different studies available if you search for adrenoleukodystrophy. The Star Beam study is also doing work specifically with boys who have cerebral symptoms. Support groups also offer information on ongoing research and clinical trials.

The Myelin project lists multiple specialists in ALD/AMN here: http://www.myelin.org/resources/aldamnspecialists.html.
You can reach out to a physician near you and/or ask a neurologist or geneticist to reach out to their colleagues.

In addition ALD connect has a link to find a specialist near you here: http://www.aldconnect.org/contact_a_disease_specialist.php.

The prevalence of X-linked adrenoleukodystrophy is estimated to be between 1:20,000 to 1:50,000. In the United States, at least 1 in 21,000 males are estimated to be affected.

Support groups are a fantastic way to meet other families affected by adrenoleukodystrophy. Many of the support groups for adrenoleukodystrophy have forums or Facebook groups that allow parents and families to connect with one another. The Internet has been a powerful tool for rare disorders, allowing people to connect across states, countries, and continents. Please see: the ALD Foundation, the Myelin Project, ALD Life, or the Adrenoleukodystrophy Online Support Group.

Many of the support groups have opportunities to take action to support awareness and research for X-linked adrenoleukodystrophy. For example, the Myelin Project has opportunities to participate in fundraisers and attend related conferences. ALD Connect offers memberships and opportunities to enroll in clinical trials.

Adrenoleukodystrophy testing, both biochemical and DNA testing, is typically done as a blood test.

There is nothing currently identified that makes X-linked adrenoleukodystrophy worse. Research suggests that other genes may play a role in making the disease more or less severe.

Some research has also suggested that a diet including Lorenzo’s Oil (a mix of oleic and erucic acid) may be beneficial to help reduce the likelihood of developing cerebral symptoms though it has not been clearly shown to reduce or slow symptoms. This oil is mostly used in combination with a moderately low-fat diet. The treatment is considered investigational at this time, and should only be done under close medical supervision.

Approximately 80-85% of women who are carriers of X-linked adrenoleukodystrophy will have increased very long chain fatty acids (VLCFA), but approximately 15-20% of carrier females will have normal levels of VLCFA. For these women, DNA testing will show if they have the same genetic change as their affected child. DNA testing for a carrier is best done when the genetic change has been identified in the affected individual. Testing for the amount of VLCFA and genetic testing will require two different blood samples as the same lab may not perform both tests.

Unfortunately, the severity of adrenoleukodystrophy cannot be predicted. Clinical symptoms, severity, and progression all differ from one person to the next.

Most commonly females will not typically show the full spectrum symptoms seen in males with an X-linked adrenoleukodystrophy diagnosis. About 20% of female carriers can experience some degree of numbness/tingling in their lower limbs or difficulty walking later in life. Symptoms in females usually resemble the adrenomyeloneuropathy type of adrenoleukodystrophy.

Carriers of adrenoleukodystrophy can have neurological symptoms. Approximately 20% of carriers have symptoms that resemble AMN (adrenomyeloneuropathy). Carriers who show symptoms usually start to show symptoms in the 30s or 40s. Additionally, their symptoms will be less severe than males who are affected with adrenoleukodystrophy.

A woman would still be encouraged to breastfeed her baby with X-linked adrenoleukodystrophy to help provide needed nutrients and assist in early bonding.

Other specific treatments for X-linked adrenoleukodystrophy will depend on the patient’s specific symptoms. For example, therapies including physical or occupational therapy may help the patient deal with symptoms of pain or spasticity.

Published healthcare guidelines for adrenoleukodystrophy can be found at http://ojrd.biomedcentral.com/articles/10.1186/1750-1172-7-51. These guidelines were published in August 2012 and serve as a comprehensive guide to the clinical presentation and management of adrenoleukodystrophy.

Adrenoleukodystrophy is also called X-linked adrenoleukodystrophy, referring to how it’s inherited or passed through families. Adrenoleukodystrophy and X-linked adrenoleukodystrophy are the most up-to-date names for the condition. It has also been called Addison disease and cerebral sclerosis, Siemerling-Creutzfeldt Diease, Bronze Schilder Disease, melanodermic leukodystrophy, Schilder-Addison Complex, and Schilder disease.

There are multiple support groups for X-linked adrenoleukodystrophy. Some of these groups include the Adrenoleukodystrophy Foundation, ALD Connect, ALD Life, the Myelin project, and the United Leukodystrophy Foundation. All of these support groups have an online presence. Additionally, the Adrenoleukodystrophy Online Support Group is a support group exclusively on the Internet.

There are multiple ways X-linked adrenoleukodystrophy can be expressed. These can be divided based on the symptoms that are present in any one particular patient. Childhood cerebral forms have an onset of ages 4-8 and symptoms include attention problems, poor school performance, difficulty in understanding speech, reading comprehension problems, clumsiness, and problems with eyesight. Children with this form may also have seizures and problems progress over time. The adrenomyeloneuropathy (AMN) form has symptoms often beginning in 20s-40s and symptoms include leg weakness, difficulties with digestion and sexual dysfunction that gets worse with time. Individuals with the Addison-disease-only type typically start showing symptoms in childhood that may include vomiting, weakness and changes in skin coloring. These problems can be helped with hormone replacement therapy.

Additional differences in presentation are seen in about 5-10% of individuals and symptoms include headache, behavior problems, memory loss, clumsiness, and/or bladder and bowel dysfunction.

Changes in the ABCD1 gene in males are considered causative, not a predisposition, for X-linked adrenoleukodystrophy, including the cerebral form, adrenomyeloneuropathy, and the Addison-disease only form. This being said, symptoms and the age that those symptoms begin can vary between individuals and some boys and men may not realize they have the gene change.

The number of people with X-linked adrenoleukodystrophy does not seem to be different among people of varying ethnic groups.

Many of the symptoms seen in adrenoleukodystrophy are also present in other disorders. Most notably, one of the earliest sign of adrenoleukodystrophy is difficulty with attention, which may lead to a diagnosis of attention deficit disorder (ADD). Attention deficit disorder has many causes, and the vast majority of cases are unrelated to adrenoleukodystrophy. Seizures can also present in adrenoleukodystrophy, but there are many causes for seizures, as well. Other leukodystrophies, such as Krabbe disease or metachromatic leukodystrophy, may also have similar symptoms to childhood cerebral X-linked adrenoleukodystrophy.

The adrenomyeloneuropathy form of adrenoleukodystrophy, which often presents with muscle weakness and tingling in the feet and legs, may look like multiple sclerosis or amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Other symptoms have overlap with Alzheimer disease, psychosis, brain tumors, and other conditions.

An individual showing the signs of adrenal insufficiency may be diagnosed with Addison’s disease. Adrenoleukodystrophy is the most common genetic cause of Addison’s disease, but most cases of Addison’s disease are not caused by adrenoleukodystrophy. Addison’s disease is often related to autoimmune disorders, infections, and can also be triggered by environmental factors, such as stopping corticosteroid medication, or changes to the pituitary gland in the brain.

Because of this overlap in symptoms, individuals with adrenoleukodystrophy may go through a "diagnostic odyssey" before they are correctly diagnosed.