X-ALD_Female (X-Linked Adrenoleukodystrophy)
Disorder name: X-LinkedA 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 female carriers?
- What is the treatment for X-ALD in female carriers?
- 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 females. 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 newborn screeningA 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 she definitely has X-ALD or is a carrier. There are usually other medical tests (for example, blood tests) that need to be done to confirm whether your baby actually has X-ALD.
WHAT IS X-ALD?
X-linked adrenoleukodystrophy (X-ALD) is an inheritedAcquiring 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 adrenal glandsThe 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 fatFat 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 focuses on female carriersA 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. For information about males with X-ALD, see our X-ALD in Males Fact Sheet.
|Peroxisomal DisordersPeople 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 cellsThe 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 enzymesA 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 proteinA 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 (very long-chain fatty acidsThis 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 peroxisomePeroxisomes 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 X chromosomeOne 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 chromosomesA 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.
GenesA 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 carriers 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 Y chromosomeOne 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 FEMALE CARRIERS?
Females who are carriers of X-ALD can sometimes show symptoms of X-ALD. However, they usually will not have as many symptoms as males who have X-ALD and develop symptoms at an older age than boys with X-ALD.
Up to 50% of female carriers of X-ALD will develop a condition called adrenomyeloneuropathy (AMN) in adulthood. AMN affects the nerves in the spinal cord and gets worse over time. Female carriers of X-ALD typically develop symptoms of AMN in their thirties or later.
Symptoms of AMN in females affect the spinal cord and peripheral nerves, and include:
- Progressive stiffness and weakness of legs
- Urge incontinence (sudden urge to urinate)
- Spastic gate (stiff, abnormal walking)
Other symptoms of ALD
Males with X-ALD may develop Addison disease (adrenal insufficiency) and cerebral ALD.
It is very rare for female carriers of X-ALD to have Addison disease or to develop cerebral ALD with less than 1% of female carriers developing these conditions. However, it is still important for female carriers to have regular monitoring and to be aware of all of the symptoms of X-ALD.
While it is very rare, if female carriers experience any symptoms for Addison disease or cerebral ALD, it is important for them to seek medical care as soon as possible.
Symptoms of Addison disease include unexplained nausea and vomiting, abdominal pain, weakness, fatigueFatigue 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., dehydrationDehydration 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., comaThis 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., and increased pigment in the skin. Addison disease usually occurs in males with X-ALD between age 2 to adulthood, typically by age 7-8.
Symptoms of cerebral ALD include behavioral and learning problems, difficulties comprehending speech, clumsiness, vision problems, hyperactivityThis 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., aggressive behavior, and seizuresThese 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.. In boys, cerebral ALD usually does not occur before the age of 3, and most commonly begins between ages of 4 to 8 and before the age of 18. Early treatment is very important in cerebral ALD.
WHAT IS THE TREATMENT OF X-ALD IN FEMALE CARRIERS?
If a female carrier of X-ALD experiences symptoms that might indicate they have Addison disease, they should be seen by an endocrinologist as soon as possible for testing for adrenal insufficiency.
If they are experiencing symptoms of cerebral ALD, they should be seen by a neurologistA specialist in the anatomy, functions, and organic disorders of nerves and the nervous system.. Regular brain MRIs are not usually recommended for female carriers of X-ALD because of how rare cerebral ALD is in females.
When they are adults, female carriers of X-ALD should consider having regular assessments by a neurologist to monitor for symptoms of adrenomyeloneuropathy, and for appropriate management as needed.
WHAT HAPPENS WHEN X-ALD IS TREATED?
Physical and occupational therapy can improve overall well-being and help to manage the symptoms of AMN.
Adrenal insufficiency, while rare, can cause major health problems. Corticosteroid replacement therapy for people with Addison disease is essential to prevent symptoms and problems associated with adrenal insufficiency.
IS GENETIC TESTING AVAILABLE?
X-ALD is caused by changes, also called variantsA 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. GeneticRelating 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. DNADeoxyribonucleic 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 ScreeningThe 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 she definitely is a carrier of 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 counselorThese 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. can help you obtain the proper tests.
Measuring VLCFA in blood from females is often not enough to determine whether a female is a carrier of X-ALD, as some carriers have normal levels of VLCFAs.
Therefore, 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 amniocentesisThis 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. 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
Baby’s First Test
National Institute of Neurological Disorders and StrokeThis 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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