Adrenoleukodystrophy
Adrenoleukodystrophy
Definition
Adrenoleukodystrophy is a progressive condition that affects the adrenal glands, the glands atop the kidneys responsible for the production of adrenalin, and myelin, which insulates the nerves in the brain and spinal cord.
Description
Adrenoleukodystrophy (ALD) was first described in the early 1900s and was originally called Schilder-Addision disease. It is named for the different parts of the body that are affected; "adreno" refers to the adrenal glands, "leuko" is the Greek word for white (myelin is often called the white matter in the brain and spinal cord) and "dystrophy" meaning impaired growth. Therefore, this disease affects the adrenal glands and the growth of the myelin in the brain and spinal cord. There is a wide range in the severity of symptoms. ALD mainly affects males, but occasionally females have mild or moderate symptoms.
Causes and effects
ALD is caused by problems in the peroxisomes. The peroxisomes are tiny structures in cells that help break down large molecules of fats into smaller ones so that they can be used by the body. In ALD the peroxisomes cannot break down a type of fat called very long chain fatty acids (VLCFA). There are two types of problems that occur because the VLCFA are not broken down. First, because the VLCFA cannot be broken down, they accumulate throughout the body, especially in the brain and the adrenal glands. Very high levels of VLCFA are also seen in the blood. The second type of problem occurs because the fats that are usually made when VLCFA are broken down are not produced. This is in part what happens in the adrenal glands and in the myelin.
The adrenal glands are located on top of each kidney in the abdomen. Part of the job of the adrenal glands is to use cholesterol (a type of fat made in the body when VLCFA are broken down) to make a few different steroids—chemical combinations that form the basis of hormones, body acids, and anabolic agents. The steroids are used to help the body properly use sodium and potassium and to break down proteins, carbohydrates, and other fats. Some of these steroids are also involved with sexual development and function.
The insulation that surrounds the nerves is called myelin and is also affected by the VLCFA not being broken down. Myelin is made up of a number of different proteins and fats. Normally the VLCFA break down and produce fats that make up part of the myelin. When the VLCFA cannot break down, the fats necessary to make the myelin are not made and the myelin is abnormal. In addition, for reasons not well understood, there is also active breakdown of myelin, also known as demyelination.
Genetic profile
ALD is caused by a mutation in a gene called the ALD gene. Genes contain the instructions for how the body grows and develops before and after a person is born. The ALD gene makes a protein called ALDP (ALD protein). Different proteins put together make the tissues and organs in the body such as myelin. ALDP is important because it helps VLCFA get into the peroxisomes. When there is a mutation in the ALD gene, the ALDP is abnormal or not present at all. As a result, the VCLFA cannot get into the peroxisomes and the VLCFA accumulate in other places in the body.
Genes are organized on structures called chromosomes. Hundreds to thousands of genes are found on each chromosome . There are 46 chromosomes in each cell of the body. These are grouped into 23 pairs. The first 22 pairs are the same in both males and females. The 23rd pair is called the sex chromosomes; having one X chromosome and one Y chromosome causes a person to be male; having two X chromosomes causes a person to be female. People get one member of each pair from the mother's egg and one member from the father's sperm.
The ALD gene is located on the X chromosome. Since males only have one X chromosome, they only have one copy of the ALD gene. Thus, when a male has a mutation in his ALD gene, he will have ALD. However, females have two X chromosomes and therefore have two copies of the ALD gene. If they have a mutation in one copy of their ALD genes, they may only have mild symptoms of ALD or no symptoms at all. This is because their normal copy of the ALD gene does make normal ALD protein. Females who have one copy of the ALD gene with a mutation and one normal copy are called carriers.
Inheritance
ALD is passed on through families by X-linked recessive inheritance . This means that affected males are related through females in the family and there are no males in the family that have passed ALD onto their sons. Females pass on one of their X chromosomes to their children—sons or daughters. For a female carrier, if her normal X chromosome is passed on, her son or daughter will be unaffected and cannot pass ALD onto their children. However, if the X chromosome with the ALD mutation is passed on, a daughter will be a carrier and the son would have ALD. Therefore, a female carrier has a 50% or one in two chance of having an unaffected child (son or daughter), a 25%, or one in four, chance of having a carrier daughter, and a 25% or one in four chance of having an affected son.
When males pass on an X chromosome, they have a daughter. When they pass on a Y chromosome, they have a son. Since the ALD mutation is on the X chromosome, an affected male will always pass the ALD mutation on to his daughters. However, when he has a son, he passes on the Y chromosome, and the son is not affected. Therefore, an affected male passes the ALD gene mutation on to all of his daughters, but none of his sons.
Demographics
ALD has been described in people from all different ethnic groups. Approximately one in 20,000 to one in 42,000 people have ALD.
Signs and symptoms
Adrenal insufficiency
Almost all individuals affected with ALD have problems with their adrenal glands not working properly. This is called adrenal insufficiency. These problems include sluggishness, weakness, weight loss, hypoglycemia, nausea, vomiting, darkening of the skin color, and mental changes. Because adrenal insufficiency can cause problems with regulating the balance of sodium and potassium in the body, a person can go into shock and a coma, which can be potentially life threatening. Since this aspect of ALD is readily treatable, it is important to identify these patients in order to prevent these complications.
Types of ALD
There is a wide range in the severity of symptoms and age of onset of ALD. All different severities have been seen within the same family. Therefore, a family who has many mildly affected members could still have a more severely affected member. ALD is roughly divided into three different types according to severity and age of onset. However, some patients do not fall neatly into one of these categories and instead fall somewhere in between. Each type is given a different name, although all have mutations (changes in the genetic code) in the same gene and the same type of inheritance.
The most severe form of ALD is called childhood ALD. About 35% of people with ALD have this type. These children usually have normal development in the first few years of life. Symptoms typically begin between four and eight years of age. Very rarely is the onset before the age of three or after the age of 15. In some boys, the first symptom may be seizures. In other children, they become hyperactive and have behavioral problems that may initially be diagnosed as attention deficit disorder. Early signs may also include poor school performance due to impaired vision that is not correctable by eyeglasses. Although these symptoms may last for a few months, other more severe problems develop. These include increasing problems with schoolwork and deterioration in handwriting and speech. They usually develop clumsiness, difficulty in reading and comprehension of written material, aggressive or uninhibited behavior, and various personality and behavioral changes. Most of these boys have problems with their adrenal glands by the time their first symptoms are noticed.
A milder form of ALD called adrenomyeloneuropathy (AMN) usually has a symptom onset at the age of 20 or later. Approximately 40–45% of people with ALD have this type. The first symptoms are typically a progressive stiffness and weakness in the legs. Problems with urination and sexual function may also develop. Symptoms slowly progress over many years. Less than 20% of men with AMN will develop significant brain involvement that leads to cognitive and behavioral problems that are severe and may cause a shortened life span. About 70% of men with AMN will have problems with their adrenal glands when other symptoms are first noticed.
A third type of ALD is called Addison disease and affects about 10% of all of those with ALD. In this condition, people do not have the neurologic symptoms associated with ALD and AMN, but do have problems resulting from adrenal insufficiency. Symptoms typically begin between two years of age and adulthood. The first symptoms are often vomiting, weakness or coma. People with Addision disease may or may not have darker skin. Many who are initially diagnosed with Addison disease will later develop symptoms of AMN.
In female carriers, about 20% will develop mild to moderate progressive stiffness and weakness in the legs and sometimes problems with urination. Rarely do they develop adrenal insufficiency. Symptoms in women generally do not begin before middle age.
Diagnosis
When the diagnosis of ALD is suspected, a test called magnetic resonance imaging (MRI) is usually required. In this test, pictures of the brain are taken and the amount of white matter (myelin) in the brain is measured. In people with symptoms of ALD, there are usually characteristic changes in the white matter. An MRI can be helpful in making the diagnosis of ALD, but if changes are seen on MRI, it does not confirm the diagnosis of ALD. Changes in the white matter may only be seen after 1–2 years of age when the brain has matured.
A definitive diagnosis of ALD can be made by measuring the level of the VLCFA in the blood. In 99.9% of males with all types of ALD, the level of the VLCFA in blood is very high. This is diagnostic of ALD.
When ALD is suspected, testing should also be performed to measure the adrenal function. In 90% of boys with symptoms of ALD and 70% of men with AMN, the adrenal glands are affected.
Approximately 85% of female carriers will have higher than normal levels of VLCFA in their blood. However, 15–20% of female carriers will have normal levels of VLCFA in their blood, which gives a "false negative" result. If a woman wants to be certain about her carrier status, genetic testing to look for a specific mutation in the ALD gene can be performed. This testing usually involves drawing a small amount of blood. Before a woman could have testing to determine her carrier status, a mutation in the ALD gene must have already been found in an affected member of the family. If a mutation in the ALD gene has already been found in another family member, testing on another child suspected on having ALD would be done to look at the mutation known to cause ALD in the family.
Treatment and management
When the diagnosis of ALD is made, an important first step is to measure the level of adrenal function. If there is adrenal insufficiency, treatment should be given by steroid replacement, which can prove to be life saving. Adrenal function should be tested periodically.
Early on, it was thought that reducing the VLCFA in a person's diet would help reduce the symptoms of ALD. Although some VLCFA does comes from diet, most of it is produced in the body. Therefore, altering the diet alone does not cure ALD.
Lorenzo's oil
In the early 1990s, a film called Lorenzo's Oil told an embellished account of a real life family who had a young son with ALD and their search to find a cure for him. A possible treatment was found and was named Lorenzo's oil, after their son, Lorenzo. The Lorenzo's oil therapy worked to reduce the level of VLCFA in the blood. The idea was that if the level of VLCFA could be reduced, perhaps it would cure or help the symptoms. After a number of years of use, Lorenzo's oil unfortunately does not seem to be an effective treatment, at least in those with advanced signs and symptoms. Although it does reduce the level of VLCFA in blood, it does not seem to alter a person's symptoms.
Bone marrow transplant
One promising treatment is bone marrow transplant. However, this is a potentially dangerous procedure that has a 10–20% rate of death. Information is available on a limited number of patients. In the very small number of patients who have had a bone marrow transplant, a few have had their condition stabilize and a few have even made slight improvements. However, all of these people had the bone marrow transplant at an early stage of their disease. This treatment does have drawbacks including the fact that there are limited numbers of donors who are a suitable "match" and a significant chance that complications will develop from the transplant. Early data suggests that bone marrow transplant is most effective when it is performed at an early stage of the disease when abnormalities are first seen through MRI. Additional long term studies are necessary to determine the overall success of these procedures.
Other treatments
Research is being done with other treatments such as lovastatin and 4-phenylbutyrate, both of which may help lower VLCFA levels in cells, but more work is necessary to determine their effectiveness. Gene therapy ,a possible method of treatment, works by replacing, changing, or supplementing non-working genes. Although different gene therapy methods are being testing on animals, they are not ready for human trials.
Other types of therapy and supportive care are of benefit to both affected boys and their families. Physical therapy can help reduce stiffness and occupational therapy can help make the home more accessible. Support from psychologists and other families who have been or are in a similar situation can be invaluable. Many men with AMN lead successful personal and professional lives and can benefit from vocational counseling and physical and occupational therapy.
Prenatal diagnosis
Prenatal testing to determine whether an unborn child is affected is possible if a specific ALD mutation has been identified in a family. This testing can be performed at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.
An experimental procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition. This procedure is only possible for those families in which a mutation in the ALD gene has been identified. Those interested in learning more about this procedure should check with their doctor or genetic counselor.
Prognosis
The prognosis for people with ALD varies depending on the type of ALD. Those diagnosed with childhood ALD usually have a very rapid course. Symptoms typically progress very fast and these children usually become completely incapacitated and die within three to five years of the onset of symptoms.
The symptoms of AMN progress slowly over decades. Most affected individuals have a normal life span.
Resources
PERIODICALS
Laan, L. A. E. M., et al. "Childhood-onset cerebral X-linked adrenoleukodystrophy." The Lancet 356 (November 4, 2000): 1608–1609.
Moser, H. W., L. Bezman, S. E. Lu, and G. V. Raymond. "Therapy of X-linked adrenoleukodystrophy: Prognosis based upon age and MRI abnormality and plans for placebo-controlled trials." Journal of Inherited Metabolic Disease 23 (2000): 273–277.
Moser, H. W. "Treatment of X-linked adrenoleukodystrophy with Lorenzo's oil." Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September, 1999): 279–280.
Shapiro, E., et al. "Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy." The Lancet 356, no. 9231 (August 26, 2000): 713–718.
Suzuki, Y., et al. "Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy." Journal of Inherited Metabolic Disease 23, no. 5 (July, 2000): 453–458.
Unterrainer, G., B. Molzer, S. Forss-Petter, and J. Berger. "Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: Implications for gene therapy of X-linked adrenoleukodystrophy." Human Molecular Genetics 9, no. 18 (2000): 2609–2616.
van Geel, B. M., et al, on behalf of the Dutch X-ALD/AMN Study Group. "Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with 'Lorenzo's oil."' Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September, 1999): 290–299.
Verrips, A., M. A. A. P. Willemsen, E. Rubio-Gozalbo, J. De Jong, and J. A. M. Smeitink. "Simvastatin and plasma very long chain fatty acids in X-linked adrenoleukodystrophy." Annals of Neurology 47, no. 4 (April, 2000): 552–553.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <http://www.ulf.org>.
WEBSITES
"Entry 300100: Adrenoleukodystrophy, (ALD)." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300100>.
Moser, Hugo W., Anne B. Moser, and Corinne D. Boehm. "X-linked adrenoleukodystrophy." (March 9, 1999). University of Washington, Seattle. GeneClinics. <http://www.geneclinics.org/profiles/x-ald/>.
Karen M. Krajewski, MS, CGC
Adrenoleukodystrophy
Adrenoleukodystrophy
Definition
Adrenoleukodystrophy is a progressive condition that affects the adrenal glands, the glands atop the kidneys responsible for the production of adrenalin, and myelin, which insulates the nerves in the brain and spinal cord.
Description
Adrenoleukodystrophy (ALD) was first described in the early 1900s and was originally called Schilder-Addision disease. It is named for the different parts of the body that are affected; "adreno" refers to the adrenal glands, "leuko" is the Greek word for white (myelin is often called the white matter in the brain and spinal cord), and "dystrophy" meaning impaired growth. Therefore, this disease affects the adrenal glands and the growth of the myelin in the brain and spinal cord. There is a wide range in the severity of symptoms. ALD mainly affects males, but occasionally females have mild or moderate symptoms.
Causes and effects
ALD is caused by problems in the peroxisomes. The peroxisomes are tiny structures in cells that help break down large molecules of fats into smaller ones so that they can be used by the body. In ALD the peroxisomes cannot break down a type of fat called very long chain fatty acids (VLCFA). There are two types of problems that occur because the VLCFA are not broken down. First, because the VLCFA cannot be broken down, they accumulate throughout the body, especially in the brain and the adrenal glands. Very high levels of VLCFA are also seen in the blood. The second type of problem occurs because the fats that are usually made when VLCFA are broken down are not produced. This is in part what happens in the adrenal glands and in the myelin.
The adrenal glands are located on top of each kidney in the abdomen. Part of the job of the adrenal glands is to use cholesterol (a type of fat made in the body when VLCFA are broken down) to make a few different steroids—chemical combinations that form the basis of hormones, body acids, and anabolic agents. The steroids are used to help the body properly use sodium and potassium and to break down proteins, carbohydrates, and other fats. Some of these steroids are also involved with sexual development and function.
The insulation that surrounds the nerves is called myelin and is also affected by the VLCFA not being broken down. Myelin is made up of a number of different proteins and fats. Normally the VLCFA break down and produce fats that make up part of the myelin. When the VLCFA cannot break down, the fats necessary to make the myelin are not made and the myelin is abnormal. In addition, for reasons not well understood, there is also active breakdown of myelin, also known as demyelination.
Genetic profile
ALD is caused by a mutation in a gene called the ALD gene. Genes contain the instructions for how the body grows and develops before and after a person is born. The ALD gene makes a protein called ALDP (ALD protein). Different proteins put together make the tissues and organs in the body such as myelin. ALDP is important because it helps VLCFA get into the peroxisomes. When there is a mutation in the ALD gene, the ALDP is abnormal or not present at all. As a result, the VCLFA cannot get into the peroxisomes and the VLCFA accumulate in other places in the body.
Genes are organized on structures called chromosomes . Hundreds to thousands of genes are found on each chromosome. There are 46 chromosomes in each cell of the body. These are grouped into 23 pairs. The first 22 pairs are the same in both males and females. The 23rd pair is called the sex chromosomes; having one X chromosome and one Y chromosome causes a person to be male; having two X chromosomes causes a person to be female. People get one member of each pair from the mother's egg and one member from the father's sperm.
The ALD gene is located on the X chromosome. Since males only have one X chromosome, they only have one copy of the ALD gene. Thus, when a male has a mutation in his ALD gene, he will have ALD. However, females have two X chromosomes and therefore have two copies of the ALD gene. If they have a mutation in one copy of their ALD genes, they may only have mild symptoms of ALD or no symptoms at all. This is because their normal copy of the ALD gene does make normal ALD protein. Females who have one copy of the ALD gene with a mutation and one normal copy are called carriers.
Inheritance
ALD is passed on through families by X-linked recessive inheritance . This means that affected males are related through females in the family and there are no males in the family that have passed ALD onto their sons. Females pass on one of their X chromosomes to their children—sons or daughters. For a female carrier, if her normal X chromosome is passed on, her son or daughter will be unaffected and cannot pass ALD onto their children. However, if the X chromosome with the ALD mutation is passed on, a daughter will be a carrier and the son would have ALD. Therefore, a female carrier has a 50% or one in two chance of having an unaffected child (son or daughter), a 25%, or one in four, chance of having a carrier daughter, and a 25% or one in four chance of having an affected son.
When males pass on an X chromosome, they have a daughter. When they pass on a Y chromosome, they have a son. Since the ALD mutation is on the X chromosome, an affected male will always pass the ALD mutation on to his daughters. However, when he has a son, he passes on the Y chromosome, and the son is not affected. Therefore, an affected male passes the ALD gene mutation on to all of his daughters, but none of his sons.
Demographics
ALD has been described in people from all different ethnic groups. Approximately one in 20,000 to one in 42,000 people have ALD.
Signs and symptoms
Adrenal insufficiency
Almost all individuals affected with ALD have problems with their adrenal glands not working properly. This is called adrenal insufficiency. These problems include sluggishness, weakness, weight loss, hypoglycemia, nausea, vomiting, darkening of the skin color, and mental changes. Because adrenal insufficiency can cause problems with regulating the balance of sodium and potassium in the body, a person can go into shock and a coma, which can be potentially life threatening. Since this aspect of ALD is readily treatable, it is important to identify these patients in order to prevent these complications.
Types of ALD
There is a wide range in the severity of symptoms and age of onset of ALD. All different severities have been seen within the same family. Therefore, a family who has many mildly affected members could still have a more severely affected member. ALD is roughly divided into three different types according to severity and age of onset. However, some patients do not fall neatly into one of these categories and instead fall somewhere in between. Each type is given a different name, although all have mutations (changes in the genetic code) in the same gene and the same type of inheritance.
The most severe form of ALD is called childhood ALD. About 35% of people with ALD have this type. These children usually have normal development in the first few years of life. Symptoms typically begin between four and eight years of age. Very rarely is the onset before the age of three or after the age of 15. In some boys, the first symptom may be seizures. In other children, they become hyperactive and have behavioral problems that may initially be diagnosed as attention deficit disorder. Early signs may also include poor school performance due to impaired vision that is not correctable by eyeglasses. Although these symptoms may last for a few months, other more severe problems develop. These include increasing problems with schoolwork and deterioration in handwriting and speech. They usually develop clumsiness, difficulty in reading and comprehension of written material, aggressive or uninhibited behavior, and various personality and behavioral changes. Most of these boys have problems with their adrenal glands by the time their first symptoms are noticed.
A milder form of ALD called adrenomyeloneuropathy (AMN) usually has a symptom onset at the age of 20 or later. Approximately 40–45% of people with ALD have this type. The first symptoms are typically a progressive stiffness and weakness in the legs. Problems with urination and sexual function may also develop. Symptoms slowly progress over many years. Less than 20% of men with AMN will develop significant brain involvement that leads to cognitive and behavioral problems that are severe and may cause a shortened life span. About 70% of men with AMN will have problems with their adrenal glands when other symptoms are first noticed.
A third type of ALD is called Addison disease and affects about 10% of all of those with ALD. In this condition, people do not have the neurologic symptoms associated with ALD and AMN, but do have problems resulting from adrenal insufficiency. Symptoms typically begin between two years of age and adulthood. The first symptoms are often vomiting, weakness, or coma. People with Addision disease may or may not have darker skin. Many who are initially diagnosed with Addison disease will later develop symptoms of AMN.
In female carriers, about 20% will develop mild to moderate progressive stiffness and weakness in the legs and sometimes problems with urination. Rarely do they develop adrenal insufficiency. Symptoms in women generally do not begin before middle age.
Diagnosis
When the diagnosis of ALD is suspected, a test called magnetic resonance imaging (MRI) is usually required. In this test, pictures of the brain are taken and the amount of white matter (myelin) in the brain is measured. In people with symptoms of ALD, there are usually characteristic changes in the white matter. An MRI can be helpful in making the diagnosis of ALD, but if changes are seen on MRI, it does not confirm the diagnosis of ALD. Changes in the white matter may only be seen after 1–2 years of age when the brain has matured.
A definitive diagnosis of ALD can be made by measuring the level of the VLCFA in the blood. In 99.9% of males with all types of ALD, the level of the VLCFA in blood is very high. This is diagnostic of ALD.
When ALD is suspected, testing should also be performed to measure the adrenal function. In 90% of boys with symptoms of ALD and 70% of men with AMN, the adrenal glands are affected.
Approximately 85% of female carriers will have higher than normal levels of VLCFA in their blood. However, 15–20% of female carriers will have normal levels of VLCFA in their blood, which gives a "false negative" result. If a woman wants to be certain about her carrier status, genetic testing to look for a specific mutation in the ALD gene can be performed. This testing usually involves drawing a small amount of blood. Before a woman could have testing to determine her carrier status, a mutation in the ALD gene must have already been found in an affected member of the family. If a mutation in the ALD gene has already been found in another family member, testing on another child suspected on having ALD would be done to look at the mutation known to cause ALD in the family.
Treatment and management
When the diagnosis of ALD is made, an important first step is to measure the level of adrenal function. If there is adrenal insufficiency, treatment should be given by steroid replacement, which can prove to be life saving. Adrenal function should be tested periodically.
Early on, it was thought that reducing the VLCFA in a person's diet would help reduce the symptoms of ALD. Although some VLCFA does come from the diet, most of it is produced in the body. Therefore, altering the diet alone does not cure ALD.
Lorenzo's oil
In the early 1990s, a film called Lorenzo's Oil told an embellished account of a real life family who had a young son with ALD and their search to find a cure for him. A possible treatment was found and was named Lorenzo's oil, after their son, Lorenzo. The Lorenzo's oil therapy worked to reduce the level of VLCFA in the blood. The idea was that if the level of VLCFA could be reduced, perhaps it would cure or help the symptoms. After a number of years of use, Lorenzo's oil unfortunately does not seem to be an effective treatment, at least in those with advanced signs and symptoms. Although it does reduce the level of VLCFA in blood, it does not seem to alter a person's symptoms.
Bone marrow transplant
One promising treatment is bone marrow transplant. However, this is a potentially dangerous procedure that has a 10–20% rate of death. As of early 2001, information is available on a limited number of patients. In the very small number of patients who have had a bone marrow transplant, a few have had their condition stabilize and a few have even made slight improvements. However, all of these people had the bone marrow transplant at an early stage of their disease. This treatment does have drawbacks including the fact that there are limited numbers of donors who are a suitable "match" and a significant chance that complications will develop from the transplant. Early data suggests that bone marrow transplant is most effective when performed at an early stage of the disease when abnormalities are first seen through MRI. Additional long-term studies are necessary to determine the overall success of these procedures.
Other treatments
Research is being done with other treatments such as lovastatin and 4-phenylbutyrate, both of which may help lower VLCFA levels in cells, but more work is necessary to determine their effectiveness. Gene therapy , a possible method of treatment, works by replacing, changing, or supplementing non-working genes. Although different gene therapy methods are being testing on animals, they are not ready for human trials.
Other types of therapy and supportive care are of benefit to both affected boys and their families. Physical therapy can help reduce stiffness and occupational therapy can help make the home more accessible. Support from psychologists and other families who have been or are in a similar situation can be invaluable. Many men with AMN lead successful personal and professional lives and can benefit from vocational counseling and physical and occupational therapy.
Prenatal diagnosis
Prenatal testing to determine whether an unborn child is affected is possible if a specific ALD mutation has been identified in a family. This testing can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.
An experimental procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition. This procedure is only possible for those families in which a mutation in the ALD gene has been identified. Those interested in learning more about this procedure should check with their doctor or genetic counselor.
Prognosis
The prognosis for people with ALD varies depending on the type of ALD. Those diagnosed with childhood ALD usually have a very rapid course. Symptoms usually progress very fast and these children typically become completely incapacitated and die within three to five years of the onset of symptoms.
The symptoms of AMN progress slowly over decades. Most affected individuals have a normal lifespan.
Resources
PERIODICALS
Laan, L. A. E. M., et al. "Childhood-onset cerebral X-linked adrenoleukodystrophy." The Lancet 356 (November 4, 2000): 1608–1609.
Moser, H. W., et al. "Therapy of X-linked adrenoleukodystrophy: Prognosis based upon age and MRI abnormality and plans for placebo-controlled trials." Journal of Inherited Metabolic Disease 23 (2000): 273–277.
Moser, H. W. "Treatment of X-linked adrenoleukodystrophy with Lorenzo's oil." Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September, 1999): 279–280.
Shapiro, E., et al. "Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleuko-dystrophy." The Lancet 356, no. 9231 (August 26, 2000): 713–718.
Suzuki, Y., et al. "Bone marrow transplantation for the treatment of X-linked adrenoleukodystrophy." Journal of Inerited Metabolic Disease 23, no. 5 (July 2000): 453–458.
Unterrainer, G., B. Molzer, S. Forss-Petter, and J. Berger. "Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy." Human Molecular Genetics 9, no. 18 (2000): 2609–2616.
van Geel, B. M., et al, on behalf of the Dutch X-ALD/AMN Study Group. "Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with 'Lorenzo's oil.'" Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September 1999): 290–299.
Verrips, A., et al. "Simvastatin and plasma very long chain fatty acids in X-linked adrenoleukodystrophy." Annals of Neurology 47, no. 4 (April 2000): 552–553.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <http://www.ulf.org>.
WEBSITES
"Entry 300100: Adrenoleukodystrophy; ALD." OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300100>.
Moser, Hugo W., MD, Ann B Moser, MD, and Corinne D Boehm, MS. "X-Linked Adrenoleukodystrophy." (March 9, 1999). University of Washington, Seattle. GeneClinics. <http://www.geneclinics.org/profiles/x-ald/>.
Karen M. Krajewski, MS, CGC
Adrenoleukodystrophy
Adrenoleukodystrophy
Definition
Adrenoleukodystrophy (ALD) is a progressive condition that affects both the adrenal glands (located atop the kidneys and responsible for the production of adrenalin) and myelin (the substance that insulates the nerves in the brain, spinal cord, and the limbs).
Description
First described in the early 1900s, adrenoleukodys-trophy was originally called Schilder-Addision disease. "Adreno" refers to the adrenal glands, "leuko" is the Greek word for white (myelin is the main component of the white matter in the brain and spinal cord), and "dystrophy" means impaired growth. This disease affects the adrenal glands and the growth of the myelin.
Types of ALD
There are three types of ALD, each with a different severity of symptoms and age of onset of ALD. All varying degrees of severity have been seen within the same family. Therefore, a family who has many mildly affected members could still have a more severely affected member. Some patients do not fall neatly into one of the three categories, and instead fall somewhere in between. Each type is given a different name, although all have mutations (changes in the genetic code) in the same gene and the same type of inheritance.
The most severe form of ALD is called childhood ALD. About 35% of people with ALD have this type. These children usually have normal development in the first few years of life. Symptoms typically begin between four and eight years of age. Very rarely is the onset before the age of three or after the age of 15. In some boys, the first symptom may be seizures . Other children become hyperactive and have behavioral problems that may initially be diagnosed as attention deficit/hyperactivity disorder (ADHD ). Early signs may also include poor school performance due to impaired vision that is not correctable by eyeglasses. Although these symptoms may last for a few months, other more severe problems develop. These include increasing problems with schoolwork and deterioration in handwriting and speech. Affected children usually develop clumsiness, difficulty in reading and comprehension of written material, aggressive or uninhibited behavior, and various personality and behavioral changes. Most affected boys have problems with their adrenal glands by the time their first symptoms are noticed.
A milder form of ALD, called adrenomyeloneuropathy (AMN), usually has a symptom onset at the age of 20 or later. Approximately 40–45% of people with ALD have AMN. The first symptoms are typically a progressive stiffness and weakness in the legs. Problems with urination and sexual function may also develop. Symptoms slowly progress over many years. Less than 20% of men with AMN will develop significant brain involvement that leads to cognitive and behavioral problems that are severe and may cause a shortened lifespan. About 70% of men with AMN will have problems with their adrenal glands when other symptoms are initially noticed.
A third type of ALD is called Addison disease and affects about 10% of all of those with ALD. In this condition, people do not have the neurologic symptoms associated with ALD and AMN, but they do have problems resulting from adrenal insufficiency. Symptoms typically begin between two years of age and adulthood. The first symptoms are often vomiting, weakness, or coma. People with Addision disease may or may not have darker skin. Many who are initially diagnosed with Addison disease will later develop symptoms of AMN.
In female carriers of ADL, about 20% will develop mild to moderate progressive stiffness and weakness in the legs and sometimes problems with urination. Rarely do they develop adrenal insufficiency. Symptoms in women generally do not begin before middle age.
Demographics
ALD is found in all ethnic groups. About one in every 100,000 people suffers from ALD. Because the most severe form, called classic ALD, is X-linked, many more males than females are affected. Women are carriers of this X-linked form of the disease and may exhibit no or only mild symptoms. Another form of the disease is called neonatal ALD; this form of ALD is not X-linked and therefore both male and female babies exhibit symptoms. An adult-onset type of the disease is commonly called adrenomyeloneuropathy.
Causes and symptoms
ALD causes problems in the peroxisomes, tiny cellular structures that are involved in breaking down large molecules of fats into smaller ones that can be used by the body. In ALD, the peroxisomes cannot break down a type of fat called very long chain fatty acid (VLCFA). As a result, VLCFAs accumulate throughout the body, particularly in the brain and adrenal glands. This accumulation interferes with the adrenal glands' conversion of cholesterol into steroids, and prompts deterioration of the myelin covering nerve cells within the white matter of the brain, thus interfering with nerve function. Additionally, fats that are usually made from the breakdown products of VLCFAs cannot be produced. Because these fats would usually be utilized in the synthesis of myelin, nerve function is further compromised.
The adrenal glands of almost all individuals affected with ALD do not secret a sufficient amount of hormones; this is called adrenal insufficiency. Symptoms include sluggishness, weakness, weight loss, hypoglycemia, nausea, vomiting, darkening of the skin color, and mental changes. Because adrenal insufficiency can cause problems with regulating the balance of sodium and potassium in the body, a person can go into shock and coma, which can be potentially life threatening. As this aspect of ALD is readily treatable, identifying these patients helps prevent these complications.
Diagnosis
When the diagnosis of ALD is suspected, the results of a test called magnetic resonance imaging (MRI) are sometimes abnormal. In this test, pictures of the brain are taken. In people with symptoms of ALD, there are usually detectable changes in the white matter. While an MRI can be helpful in making the diagnosis of ALD, a normal MRI does not exclude the diagnosis and an abnormal MRI does not definitively make the diagnosis of ALD.
A more definitive diagnosis of ALD can be made by measuring the level of the VLCFA in the blood. In nearly all males with ALD, the level of the VLCFA in blood is very high.
When ALD is suspected, testing should also be performed to measure the adrenal function. In 90% of boys with symptoms of ALD and 70% of men with AMN, the adrenal glands are affected.
Approximately 85% of female carriers will have higher than normal levels of VLCFA in their blood. However, 15–20% of female carriers will have normal levels of VLCFA in their blood, which gives a "false negative" result. If a woman wants to be certain about her carrier status, genetic testing to look for a specific mutation in the ALD gene can be performed. Before a woman could have testing to determine her carrier status, a mutation in the ALD gene must have already been found in an affected member of the family.
Treatment team
A number of professionals can provide supportive (though not curative) care for patients with adrenoleuko-dystrophy: neurogeneticists, to help with diagnosis; pediatric or adult neurologists (depending on the type of ALD and age of onset) to monitor and manage the neurological effects; pediatric or adult endocrinologists to manage the adrenal complications; and pediatric or adult urologists to manage bladder complications in both children and adults and sexual problems in adults. In addition, physical therapists, occupational therapists, speech therapists, learning specialists, and behavioral psychologists may be helpful.
Treatment
When the diagnosis of ALD is made, an important first step is to measure the level of adrenal function. If there is adrenal insufficiency, treatment should be given by steroid replacement, which can prove to be lifesaving. Adrenal function should be tested periodically.
Lorenzo's oil
In the early 1990s, a film called Lorenzo's Oil presented a fictionalized account of a real ALD patient, a young boy named Lorenzo, and his family's search to find a cure for him. A possible treatment was found and was named Lorenzo's oil. The Lorenzo's oil therapy worked to reduce the level of VLCFA in the blood. The idea was that if the level of VLCFA could be reduced, perhaps it would cure or help the symptoms. After a number of years of use, Lorenzo's oil unfortunately does not seem to be an effective treatment, at least in those with advanced signs and symptoms. Although it does reduce the level of VLCFA in blood, it does not seem to alter a person's symptoms.
Bone marrow transplant
One promising treatment is bone marrow transplant. However, this is a potentially dangerous procedure that has a 10–20% rate of death. As of early 2001, information is available on a limited number of patients. In the very small number of patients who have had a bone marrow transplant, a few had their condition stabilize and a few even made slight improvements. However, all of these people had the bone marrow transplant at an early stage of their disease. This treatment does have drawbacks, including the fact that there are limited numbers of donors who are a suitable match and a significant risk that complications will develop from the transplant. Early data suggests that bone marrow transplant is most effective when it is performed at an early stage of the disease when neurological abnormalities are mild. Additional long-term studies are necessary to determine the overall success of these procedures.
Other treatments
Research is being done with other treatments such as lovastatin and 4-phenylbutyrate, both of which may help lower VLCFA levels in cells, but more work is necessary to determine their effectiveness. Gene therapy , a possible method of treatment, works by replacing, changing, or supplementing non-working genes. Although different gene therapy methods are being tested on animals, they are not ready for human trials.
Other types of therapy and supportive care are of benefit to both affected boys and their families. Physical therapy can help reduce stiffness and occupational therapy can help make the home more accessible. Support from psychologists and other families who have been or are in a similar situation can be invaluable. Many men with AMN lead successful personal and professional lives and can benefit from vocational counseling and physical and occupational therapy.
Prenatal diagnosis
Prenatal testing to determine whether an unborn child is affected is possible if a specific ALD mutation has been identified in a family. This testing can be performed at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the fetus and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.
An experimental procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition. This procedure is only possible for those families in which a mutation in the ALD gene has been identified.
Clinical Trials
A number of clinical trials are underway, including testing the efficacy of Lorenzo's oil (combination glyceryl trierucate and glyceryl trioleate), oral bile acid therapy with cholic acid, chenodeoxycholic acid, and ursodeoxycholic acid, and bone marrow or umbilical cord blood transplantation.
Prognosis
The prognosis for people with ALD is highly variable. Those diagnosed with childhood ALD usually have a very rapid course. Symptoms typically progress very fast and these children usually become completely incapacitated and die within three to five years of the onset of symptoms.
The symptoms of AMN progress slowly over decades. Most affected individuals have a normal lifespan.
Resources
PERIODICALS
Laan, L. A. E. M., et al. "Childhood-onset Cerebral X-linked Adrenoleukodystrophy." The Lancet 356 (November 4, 2000): 1608–1609.
Moser, H. W., L. Bezman, S. E. Lu, and G. V. Raymond. "Therapy of X-linked Adrenoleukodystrophy: Prognosis Based Upon Age and MRI Abnormality and Plans for Placebo-controlled Trials." Journal of Inherited Metabolic Disease 23 (2000): 273–277.
Moser, H. W. "Treatment of X-linked Adrenoleukodystrophy with Lorenzo's Oil." Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September 1999): 279–280.
Shapiro, E., et al. "Long-term Effect of Bone Marrow Transplantation for Childhood-onset Cerebral X-linked Adrenoleukodystrophy." The Lancet 356, no. 9231 (August 26, 2000): 713–718.
Suzuki, Y., et al. "Bone Marrow Transplantation for the Treatment of X-linked Adrenoleukodystrophy." Journal of Inherited Metabolic Disease 23, no. 5 (July 2000): 453–458.
Unterrainer, G., B. Molzer, S. Forss-Petter, and J. Berger. "Co-expression of Mutated and Normal Adrenoleukodystrophy Protein Reduces Protein Function: Implications for Gene Therapy of X-linked Adrenoleukodystrophy." Human Molecular Genetics 9, no. 18 (2000): 2609–2616.
Van Geel, B. M., et al, on behalf of the Dutch X-ALD/AMN Study Group. "Progression of Abnormalities in Adrenomyeloneuropathy and Neurologically Asymptomatic X-linked Adrenoleukodystrophy Despite Treatment with 'Lorenzo's Oil.'" Journal of Neurology, Neurosurgery and Psychiatry 67, no. 3 (September 1999): 290–299.
Verrips, A., M. A. A. P. Willemsen, E. Rubio-Gozalbo, J. De Jong, and J. A. M. Smeitink. "Simvastatin and Plasma Very Long Chain Fatty Acids in X-linked Adrenoleukodystrophy." Annals of Neurology 47, no. 4 (April 2000): 552–553.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673; Fax: (203) 746-6481. (May 9, 2004.) <http://www.rarediseases.org>.
United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483; Fax: (815) 895-2432. (May 9, 2004.) <http://www.ulf.org>.
WEBSITES
"Entry 300100: Adrenoleukodystrophy, (ALD)." OMIM—Online Mendelian Inheritance in Man. (May 9, 2004.) <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300100>.
Moser, Hugo W., Anne B. Moser, and Corinne D. Boehm. "X-linked Adrenoleukodystrophy." March 9, 1999 (May 9, 2004). University of Washington, Seattle. GeneClinics. <http://www.geneclinics.org/profiles/x-ald/>.
Karen M. Krajewski, MS, CGC
Rosalyn Carson-DeWitt, MD
Adrenoleukodystrophy
Adrenoleukodystrophy
Definition
Adrenoleukodystrophy is a rare genetic disease characterized by a loss of myelin surrounding nerve cells in the brain and progressive adrenal gland dysfunction.
Description
Adrenoleukodystrophy (ALD) is a member of a group of diseases, leukodystrophies, that cause damage to the myelin sheath of nerve cells. Approximately one in 100,000 people is affected by ALD. There are three basic forms of ALD: childhood, adult-onset, and neonatal. The childhood form of the disease is the classical form and is the most severe. Childhood ALD is progressive and usually leads to total disability or death. It affects only boys because the genetic defect is sex-linked (carried on the X chromosome). Onset usually occurs between ages four and ten and can include many different symptoms, not all of which appear together. The most common symptoms are behavioral problems and poor memory. Other symptoms frequently seen are loss of vision, seizures, poorly articulated speech, difficulty swallowing, deafness, problems with gait and coordination, fatigue, increased skin pigmentation, and progressive dementia.
The adult-onset form of the disease, also called adrenomyeloneuropathy, is milder, progresses slowly, is usually associated with a normal life span, and usually appears between ages 21-35. Symptoms may include progressive stiffness, weakness, or paralysis of the lower limbs and loss of coordination. Brain function deterioration may also been seen. Women who are carriers of the disease occasionally experience the same symptoms, as well as others, including ataxia, hypertonia (excessive muscle tone), mild peripheral neuropathy, and urinary problems. The neonatal form affects both male and female infants and may produce mental retardation, facial abnormalities, seizures, retinal degeneration, poor muscle tone, enlarged liver, and adrenal dysfunction. Neonatal ALD usually progresses rapidly.
Causes and symptoms
The genetic defect in ALD causes a decrease in the ability to degrade very long chain fatty acids. These build up in the adrenal glands, brain, plasma, and fibroblasts. The build-up of very long chain fatty acids interferes with the ability of the adrenal gland to convert cholesterol into steroids and causes demyelination of nerves in the white matter of the brain. Demyelinated nerve cells are unable to function properly.
Diagnosis
Diagnosis is made based on observed symptoms, a biochemical test, and a family history. The biochemical test detects elevated levels of very long chain fatty acids in samples from amniocentesis, chorionic villi, plasma, red blood cells, or fibroblasts. A family history may indicate the likelihood of ALD because the disease is carried on the X-chromosome by the female lineage of families.
Treatment
Treatment for all forms of ALD consists of treating the symptoms and supporting the patient with physical therapy, psychological counseling, and special education in some cases. There is no cure for this disease, and there are no drugs that can reverse demyelination of nerve and brain cells. Dietary measures consist of reducing the intake of foods high in fat, which are a source of very long chain fatty acids. A mixture called Lorenzo's Oil has been shown to reduce the level of long chain fatty acids if used long term; however, the rate of myelin loss is unaffected. Experimental bone marrow transplantation has not been very effective.
Prognosis
Prognosis for childhood and neonatal ALD patients is poor because of the progressive myelin degeneration. Death usually occurs between one and ten years after onset of symptoms.
Prevention
Since ALD is a genetic disease, prevention is largely limited to genetic counseling and fetal monitoring through amniocentesis or chorionic villus sampling.
Resources
BOOKS
Berkow, Robert. Merck Manual of Medical Information. Whitehouse Station, NJ: Merck Research Laboratories, 1997.
KEY TERMS
Amniocentesis— The collection of amniotic fluid through a needle inserted through the abdomen. Used to collect fetal cells for genetic analysis.
Ataxia— Loss of coordination of muscular movement.
Hypertonia— Having excessive muscular tone.
Myelin— A layer that encloses nerve cells and some axons and is made largely of lipids and lipoproteins.
Neuropathy— A disease or abnormality of the peripheral nerves.