Disorder name: A mode of inheritance. X-linked genes are found on the X chromosome. They have a different inheritance pattern than other genes because women have two X chromosomes while men only have one. Any mutation on the X chromosome may not cause a disease in women if the gene on the other chromosome is normal. However, that same mutation on one X chromosome in men will cause the disease because they have no second copy of the gene to compensate. Adrenoleukodystrophy
- What is X-ALD?
- What causes X-ALD?
- How is X-ALD inherited?
- What are the symptoms of X-ALD in males?
- What is the treatment for X-ALD in males?
- What happens when X-ALD is treated?
- Is genetic testing available?
- What other testing is available?
- Can you test for X-ALD during a future pregnancy?
- Can other members of the family have X-ALD or be carriers?
- Can other family members be tested?
- How many people have X-ALD?
- Does X-ALD happen more often in a certain ethnic group?
- Does X-ALD go by any other names?
- Where can I find more information?
This fact sheet has general information about X-Linked Adrenoleukodystrophy (X-ALD) in males (boys, men). Every child is different and some of this information may not apply to your child specifically. Certain treatments may be recommended for some children but not others. If you have specific questions about X-ALD and available treatments, you should contact your doctor.
If your newborn has had a positive screen for X-ALD after A screening test that looks for different disorders using a small sample of blood taken from a newborn’s heel. A positive or abnormal newborn screening result means that there are slight differences that were found in the baby’s blood, and further testing is needed to figure out if the baby has a metabolic disorder., it does not yet mean that he definitely has X-ALD. There are usually other medical tests (for example, blood tests) that need to be done to confirm whether your baby actually has X-ALD.
To watch a video that includes a summary of some information included in this written factsheet, you can visit https://youtu.be/gRoTOcaRRn4.
WHAT IS X-ALD?
X-linked adrenoleukodystrophy (X-ALD) is an Acquiring a trait from one’s parents. Most traits, such as eye color or hair color, are inherited from a parent through genes. condition that affects the brain, nervous system, and The adrenals are a pair of glands near the kidneys that make three types of hormones important in helping the body function normally. The main hormones made in the adrenal glands are cortisol, aldosterone and sex-hormones such as estrogen, progesterone, and male-like androgens (including testosterone). When the adrenal glands make more or less of one or more of these hormone, health problems occur.. People with X-ALD have problems breaking down a certain type of Fat is one of the three main nutrients in food (carbohydrates, fat, protein). Some foods that contain fat are butter, margarine, oils, nuts, meats, poultry, fish and some dairy products. Extra calories from food are stored as body fat. Stored body fat provides the body with a reserve supply of energy.. X-ALD is the most common type of peroxisomal disorder.
X-ALD mainly affects males, but females who are carriers of X-ALD can also develop symptoms. This fact sheet is focused on X-ALD in males. For information about X-ALD in females, please see the X-ALD Fact Sheet for Females.
|People with peroxisomal disorders have missing or non-working enzymes/proteins in their peroxisome. As a result, they have problems breaking down certain large molecules into usable forms. This leads to a build-up of these molecules, which causes a variety of health problems.:
Peroxisomes are like recycling centers for The smallest living unit. Cells make up all organs and tissues in multi-cellular organisms, like humans. They can also live independently, as in bacteria and other microorganisms. At a minimum, a cell is surrounded by a membrane, contains DNA at some stage in its life, and is able to replicate itself into two equal parts.. They are small sacs filled with A molecule that helps chemical reactions take place. For example, enzymes in the stomach speed up the process of breaking down food. Each enzyme can participate in many chemical reactions without changing or being used up. and proteins that do different jobs. Some enzymes help to break down large molecules into smaller molecules that the body can use. Other proteins help to transport molecules into the peroxisomes. People with peroxisomal disorders have missing or non-working enzymes/proteins. As a result, these people have problems breaking down certain large molecules into usable forms. This leads to a buildup of these molecules, which causes a variety of problems. The symptoms and treatment vary between different peroxisomal disorders. They can also vary from person to person with the same peroxisomal disorder.
WHAT CAUSES X-ALD?
X-ALD occurs when a A molecule that makes up many parts of every cell in the body. Examples of proteins include hormones, enzymes, hair, and antibodies. Proteins are made up of 20 different types of individual units called amino acids. It is the order of these amino acids in a protein that determines what form and function a protein has. Each gene holds the instructions for making a single protein. called adrenoleukodystrophy protein (ALDP) is either missing or not working properly. This protein’s job is to transport certain fats (This is one of many types of fatty acids, the building blocks of fat. Very long-chain fatty acids are made up of chains of 21 to 32 carbon atoms., or VLCFAs) from the body into the Peroxisomes are like recycling centers for cells. They are small sacs filled with enzymes and proteins that do different jobs. Some enzymes help to break down larger molecules into smaller molecules that the body can use. Other proteins help to transport molecules into the peroxisomes. so they can be broken down. When ALDP is not working, VLCFAs build up and can be very harmful to different parts of the body. This buildup of VLCFAs causes the symptoms of X-ALD.
The gene that tells our cells to make ALDP is called ABCD1.
HOW IS X-ALD INHERITED?
X-ALD is inherited in an X-linked pattern. In some families, an affected baby is the first person in the family to have a non-working copy of ABCD1. In those babies, X-ALD is not inherited from a parent.
In this type of inheritance, the gene associated with the condition is located on the One of the two chromosomes that are responsible for determining the sex of an organism. The other sex chromosome is called the Y chromosome. Both the X and the Y chromosome contain several genes, only some of which are involved in determining sex. In humans, the X chromosome is the larger of the two sex chromosomes. Females usually have two X chromosomes and males usually have one X chromosome and one Y chromosome., which is one of the sex A strand of DNA contained within a cell. Each chromosome contains many thousands of genes. In humans, there are a total of 46 chromosomes, half of which come from each parent. The combined total of all chromosomes in a cell is the genome.. X-ALD is caused by changes in the ABCD1 gene which is located on the X chromosome.
A segment of DNA that contains the instructions to make a specific protein (or part of a protein). Genes are contained on chromosomes. Chromosomes, and the genes on those chromosomes, are passed on from parent to child. Errors in the DNA that make up a gene are called variants and can lead to diseases. usually come in pairs, with each parent giving one copy to their child. The sex chromosomes, however, are different. A male inherits one X chromosome from his mother, and one Y chromosome from his father. Males have only one X chromosome. A female inherits two X chromosomes, one from each parent.
A male with a non-working ABCD1 gene on his X chromosome will have X-ALD. This is because he does not have a second X chromosome with a working copy of the ABCD1 gene. Therefore, it is more common for males to have X-ALD than females.
When a female has a non-working copy of the ABCD1 gene on one of her X chromosomes, she will be a carrier of X-ALD. She has a second, working copy of the ABCD1 gene on her other X chromosome. Female A person who has one copy of a gene mutation for a particular autosomal recessive disorder (remember genes come in pairs). Carriers are not affected by the disorder. However, they can pass on the gene variant to their children. Children who inherit two such gene variants will be affected by the disorder. The term variants is now used in place of the term mutation. of X-ALD most often will not have symptoms of X-ALD, but if she does, they are usually not as severe as males.
Source: OpenStax CNX
If a mother has one non-working copy of the ABCD1 gene, she is called a carrier. For carriers, there is a 50% chance that each male pregnancy will have X-ALD (affected son). For carriers, there is a 50% chance that each female pregnancy will be a carrier (carrier daughter), like her mother.
A father passes his One of the two sex chromosomes that is responsible for determining the sex of an organism. The other sex chromosome is called the X chromosome. Both the X and the Y chromosome contain several genes, only some of which are involved in determining sex. In humans, the Y chromosome is the smaller of the two sex chromosomes. Most females have two X chromosomes and most males have one X chromosome and one Y chromosome. to his sons and his X chromosome to his daughters. Therefore, if a father has X-ALD, none of his sons will have X-ALD and all of his daughters will be carriers.
WHAT ARE THE SYMPTOMS OF X-ALD IN MALES?
The symptoms of X-ALD vary from person to person and can begin at different ages, ranging from infancy to middle age. It is important to remember that every child with X-ALD is different and it is not possible to predict how severely a child may be affected.
There are three major symptom sets, or ‘presentations,’ of X-ALD in males.
1. Addison disease (adrenal insufficiency)
Adrenal insufficiency, also known as Addison disease, usually occurs in males with X-ALD between age 2 to adulthood, typically by age 7-8. About 80% of males with X-ALD will develop adrenal sufficiency before adulthood, and almost all males with X-ALD will develop it at some point in their life.The adrenal glands are responsible for producing some Hormones include many different types of chemicals that act as messengers around the body. Hormones are made by specific endocrine glands and are secreted into the blood when needed by other parts of the body. Hormones travel to other organs and tissues in the body to signal them to do something. For example, insulin is a hormone that signals muscle and fat cells to remove glucose from the blood and enter the cells.. Adrenal insufficiency causes a shortage of certain hormones in the body.Initial symptoms of adrenal insufficiency include:
- Nausea and vomiting, abdominal pain
- Weakness and Fatigue is a feeling of weariness, tiredness, or lack of energy. Fatigue can be a normal and important response to physical exertion, emotional stress, or lack of sleep. However, it can also be a sign of a more serious health disorder., loss of appetite
- Dehydration occurs when a person loses more water than they take in. Symptoms of dehydration are vague and include thirst, lightheadedness and diarrhea. Extreme dehydration requires hospitalization. In people with sickle cell disease, dehydration can trigger a crisis. Dehydration can be prevented by drinking plenty of water, especially when the individual is ill, in hot temperatures or participating in physical activity.
- This is a sleep-like condition from which a person cannot be awakened. People in a coma are unconscious. A coma can be caused by many things. Two causes are untreated low blood sugar (hypoglycemia) and a metabolic crisis.
- Increased skin pigmentation
Most boys with X-ALD who only have adrenal insufficiency in childhood will develop adrenomyeloneuropathy later in life.
Adrenomyeloneuropathy (AMN) occurs in virtually all men with X-ALD. However, the age of onset and rate of progression can vary. Typically, AMN is diagnosed between 20-30 years of age. AMN affects the nerves in the spinal cord and gets worse over time.Symptoms in affected include:
- Progressive stiffness and weakness of legs
- Urge incontinence (sudden urge to urinate)
- Spastic gate (stiff, abnormal walking)
- Early balding
About 70% of men with AMN also have Addison disease. Between 10-20% of men with AMN will develop cerebral ALD. We cannot predict which men with AMN will develop cerebral ALD, or at what age they will develop it.
3. Cerebral ALD
Cerebral ALD can occur in childhood, adolescence, or adulthood. Symptoms of cerebral ALD can be rapidly progressive. A newborn baby boy has a 35-40% risk of developing childhood cerebral ALD (before the age of 18). Cerebral ALD usually does not occur before the age of 3, and most commonly begins between ages of 4 to 8.
Symptoms in affected males include:
- Behavioral or learning problems, sometimes diagnosed as attention deficit disorder or This refers to children who are unusually overactive. These children have serious problems sitting still. They tend to fidget and run around much more than usual. Some children with hyperactivity need treatment. They may be helped by behavior treatment, medication or both of these therapies. (ADHD)
- “Spacing out” in school, inattention
- Deteriorating handwriting skills
- Difficulty understanding speech, reading, comprehension of writing
- Clumsiness, visual problems
- Aggressive behavior
- These are also called "convulsions" or "fits." During a seizure, a person loses consciousness and control of his or her muscles. It may also cause involuntary movements. Seizures can happen for many reasons. Some causes are metabolic disorders, a metabolic crisis, brain injury, and infection.
Without early The process of testing for a disease in a person who does not show the disease (non-symptomatic or asyntomatic). The goal of screening is to find the disease in its most important stages. and treatment, cerebral ALD can progress rapidly and cause total disability within six months to two years, and can be fatal at an average of two years after symptoms begin.
Occasionally, symptoms are more atypical and do not fit one of these presentations. Other symptoms could include headaches, visual problems, speech problems, paralysis, dementia, poor coordination and balance, and inability to control urine and bowel movements. Some patients have not had any symptoms at all.
WHAT IS THE TREATMENT FOR X-ALD IN MALES?
People with X-ALD should be treated by a team of specialists who are familiar with the disorder. This may include an endocrinologist (hormone doctor), A specialist in the anatomy, functions, and organic disorders of nerves and the nervous system. (brain doctor), neuromuscular specialist (muscle doctor), geneticist (genetics doctor) such as a A doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They are often known as Biochemical Geneticists. They often work in university hospitals or large medical centers. or This is a doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They often work in university hospitals or large medical centers., rehabilitation specialist (i.e., physical therapist), and a These are health care providers who have special training in genetic conditions. They help families understand genetic disorders and how they are passed down. Genetic counselors offer information and support to people who have genetic conditions in their families or are concerned that they may have a child with an inherited disorder.. Certain treatments may be advised for some children but not others, and some treatments are only recommended once the different symptoms associated with X-ALD occur.
It is very important that your child is regularly monitored for the development of symptoms of X-ALD, which can occur at any age.
The following monitoring and treatments are usually recommended for males with X-ALD.
- Brain This test uses magnetic waves to make pictures of the body. It can sometimes be used instead of x-rays to look at areas inside the body. It is often used to look at the brain or other inner organs.
It is very important for males with X-ALD to have a brain MRI to check for cerebral ALD starting at age 1. From age 3 to age 10, brain MRIs should be done every 6 months as this is the high-risk period for developing cerebral X-ALD; after age 10 and until age 18, brain MRIs should be done yearly. Signs of cerebral ALD can be seen on brain MRIs before symptoms develop, and early detection of cerebral ALD is vital for potential treatment.
- Hematopoietic Stem Cell Transplant In this procedure, stem cells from bone marrow, blood, or umbilical cord blood are taken from another person (donor) and implanted into the patient. The patient and donor must be a genetic match. There are many risks associated with stem cell transplants.
Hematopoietic stem cell transplant is the only way to treat cerebral ALD, and if it is successful, the progression of cerebral ALD will stop. HSCT is only recommended for males who show signs of cerebral ALD on MRIs, but are still in the early stages of cerebral disease.
- Treatment of Addison disease
Addison disease occurs when the adrenal glands do not produce the level of hormones that they should. Newborn males with X-ALD should have an initial blood test to check for adrenal insufficiency. They should then have blood testing for adrenal insufficiency every 6 months, and a yearly exam by an This is a doctor with special training in endocrine conditions –disorders caused by problems with one or more endocrine glands and their hormones. Some of the endocrine glands in the body include the adrenal glands above the kidneys, the pituitary glands, the pancreatic islets, and the thyroid glands. Some endocrine conditions include diabetes, hypothyroidism and congenital adrenal hyperplasia.. If someone with X-ALD is found to have adrenal insufficiency, this is treated with corticosteroid replacement therapy (oral medication).
- Treatment of Adrenomyeloneuropathy (AMN)
Physical therapy can help to relieve symptoms like muscle spasms and reduce muscle rigidity that develops in AMN. Occupational therapy can help develop and maintain motor skills needed for daily living and work tasks. Some medications may also be prescribed to treat nerve pain, abnormal movement, and bladder control problems.
There are other therapies that have been tried for X-ALD, some of these therapies are still under research investigation.
WHAT HAPPENS WHEN X-ALD IS TREATED?
Adrenal insufficiency can cause major health problems. Corticosteroid replacement therapy for people with Addison disease is essential to prevent symptoms and problems associated with adrenal insufficiency.
HSCT in males with early cerebral ALD can stop the progression of cerebral ALD, which is the main cause of death in X-ALD. The best results of HSCT are seen in males where the beginning of brain changes are seen on MRIs but before any symptoms are seen. HSCT does not treat or cure adrenal insufficiency. It is not yet known for certain if successful HSCT has an impact on the development of AMN.
Physical and occupational therapy can improve overall well-being and help to manage the symptoms of AMN.
IS GENETIC TESTING AVAILABLE?
X-ALD is caused by changes, also called A variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation. in the ABCD1 gene. Relating to (or due to) genes and heredity or the field of studying genes and heredity. testing, also called DNA testing, can be done on a blood sample, and looks for variants in the ABCD1 gene. Deoxyribonucleic acid (DNA) is a molecule found in the chromosomes that carries genetic information. DNA is composed of four units (called bases) that are designated A, T, G, and C. The sequence of the bases spell out instructions for making all of the proteins needed by an organism. A gene is a section of DNA that holds the instructions for a specific protein. A change in one or more of the DNA bases making up a gene is called a mutation. Some mutations change the protein instructions and can lead to particular health problems or disorders. Each parent passes half of their chromosomes, and thus half of their DNA instructions, onto their children. It is these instructions that cause certain traits, such as eye or hair color, to be inherited. testing for X-ALD is typically done to confirm the diagnosis.
DNA testing can also be helpful for carrier testing or prenatal diagnosis, discussed below.
If a genetic variant in the ABCD1 gene is not found, additional biochemical testing or genetic testing for other genetic disorders may be necessary.
WHAT OTHER TESTING IS AVAILABLE?
Newborn The process of testing for disease in a person who does not show signs of having the disease (nonsymptomatic or asymptomatic person). The goal of screening is to catch the disease in its early stages.
Newborn screening for X-ALD is only done in some states. A blood spot from a needle prick on a baby’s heel is used to screen for many different conditions. Newborn screening detects X-ALD by looking for the amount of a certain type of VLCFA in the blood spot.
If a baby has a positive result on the initial X-ALD newborn screen, it does not yet mean that he or she definitely has X-ALD. The increased amount of VLCFA can also indicate other types of peroxisomal disorders or other genetic conditions. A positive screening result is followed up by repeat testing of VLCFA in blood, and often DNA testing to confirm the diagnosis.
When someone else in the family has been diagnosed with X-ALD, newborn screening results are not enough to rule out X-ALD disease in a newborn baby. In this case, more sensitive diagnostic testing should be done in addition to newborn screening, even if the newborn screening result is negative. Your healthcare provider or genetic counselor can help you obtain the proper tests.
Measuring the concentration of VLCFA in blood in males who show symptoms can usually be enough to diagnose X-ALD.
Genetic testing of the ABCD1 gene is often necessary after a positive newborn screening result.
CAN YOU TEST FOR X-ALD DURING A FUTURE PREGNANCY?
If a genetic variant is found in the ABCD1 gene that causes X-ALD in your family has been identified, DNA from the fetus can be tested. The sample for this testing is obtained by either CVS or This is a test done during pregnancy. A needle is used to remove a small sample of fluid from the sac around the fetus. The sample can be used to test for certain genetic disorders in the fetus. Amniocentesis to test for genetic conditions is usually done between 13 and 20 weeks of pregnancy..
Parents may choose to have testing during pregnancy or wait until after birth to have the baby tested. Parents may also choose to use assisted reproductive techniques to decrease the chance that their future children would have X-ALD. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.
CAN OTHER MEMBERS OF THE FAMILY HAVE X-ALD OR BE CARRIERS?
Only some states offer newborn screening for X-ALD. It is very important that other family members are told that they could be at risk of having X-ALD or being carriers. A healthcare provider or genetic counselor can help them obtain expanded newborn screening.
Each full brother (same mother and father) of a baby with X-ALD has a 50% (1 in 2) chance of having X-ALD, even if they have had no symptoms. Finding out whether other children in the family have X-ALD is important because early treatment can prevent more serious health problems. Talk to your doctor or genetic counselor about testing your other children for X-ALD.
In addition, the father of a female baby who is found to be a carrier of X-ALD after newborn screening could also have X-ALD and not yet noticed or experienced any symptoms. It is important for both parents of a female carrier of X-ALD to be tested.
The mother of a boy with X-ALD is usually, but not always, a carrier of X-ALD. It is important for mothers to have carrier testing to determine the chance of other children or future pregnancies also having X-ALD. It is also important because mothers who are carriers of X-ALD can develop some symptoms of the condition and should have regular follow-up.
If the mother is found to be a carrier, her daughters have a 50% risk to be carriers as well.
CAN OTHER FAMILY MEMBERS BE TESTED?
If the genetic variant has been found in your child, other male family members can have DNA testing as well to see if they have X-ALD. Other blood tests may be recommended in addition to DNA testing. Other female family members can also consider DNA testing to see if they are carriers. This testing could also be important for extended family members.
HOW MANY PEOPLE HAVE X-ALD?
About 1 in 20,000 individuals are born with X-ALD.
DOES X-ALD HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?
No, X-ALD does not happen more often in any specific race, ethnic group, geographical area, or country.
DOES X-ALD GO BY ANY OTHER NAMES?
X-ALD is sometimes referred to as:
- Addison disease with cerebral sclerosis
- Adrenoleukodystrophy (ALD)
- Adrenomyeloneuropathy (AMN)
- Siemerling-Creutzfeldt disease
- Addison-Schilder disease
WHERE CAN I FIND MORE INFORMATION?
Genetics Home Reference
National Institute of Neurological Disorders and This is when the blood or oxygen supply to part of the brain is stopped. It can be caused either by a blood clot or a leak in a blood vessel. A stroke may cause loss of speech and language and the ability to move certain body parts. If severe, it can cause death.
The Stop ALD Foundation
|Reviewed by:||HI, CA, OR, and WA metabolic specialists|
|Review date:||June 9, 2020
March 30, 2018
|Update on:||June 9, 2020|
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