Amyotrophic Lateral Sclerosis Genetic Testing Basics - Medicine and Health

Amyotrophic Lateral Sclerosis

What is amyotrophic lateral sclerosis (ALS)?
Amyotrophic lateral sclerosis (ALS) is more commonly known as Lou Gehrig's disease. It was named after a famous baseball player who contracted the disease. ALS causes destruction of the nerve cells responsible for coordinating communication between the brain, spinal cord and muscles. When muscles no longer receive information from the spinal cord, they begin to shrink. People with ALS lose the ability to control their muscles. The disease does not affect a person's mental abilities. ALS is a progressive disorder because it continues to get worse over time.

People with ALS typically experience the following symptoms:

Muscle weakness
Muscle twitching
Muscle wasting
Poor coordination or clumsiness
Muscle cramps
Difficulty speaking or swallowing
Increased or decreased reflexes (caused by unhealthy nerves)
Muscles that become more rigid
Only about 5% to 10% of ALS cases are inherited. The other 90% not caused by genetics are called sporadic. The average age for someone to first see symptoms of sporadic ALS is 56. People with ALS that is genetic (it runs in the family) see their symptoms start at about age is 46. Symptoms for both causes of the disease may appear earlier or later in life.

Although ALS does not occur in distinct stages, the symptoms are progressive, meaning they get more severe over time. Symptoms depend upon which nerve groups have been damaged or destroyed.

Early stages — The first signs of ALS are often clumsiness or weakness of the hands and arms or weakness of the muscles that control speech and swallowing.
Later stages — The leg muscles become weak and poorly coordinated. Other muscles, such as those that control speech and swallowing, may become impaired.
Long term — The entire body begins to weaken and shut down. Vital muscle functions, such as breathing, become impaired. This typically leads to death.
In most cases, ALS causes death a few years after symptoms begin. With inherited ALS, the disease may progress more slowly.

How common is ALS?
Every year, between one and two people out of 100,000 are diagnosed with ALS. The disease affects men slightly more than women (about four men for every three women). In a country the size of the United States, 3,000 to 6,000 new cases per year are reported.

Who is at risk of ALS?
In most cases of ALS, there is no way to tell if someone is at risk. About 90% of ALS cases are sporadic, meaning the affected person does not have a family history of the disease or anything else that would put him or her at increased risk. In the other 10% of ALS cases, called familial, the disease runs in the family. Researchers do not know the cause of ALS or why it has genetic and non-genetic varieties.

Is my ethnic background the key to my risk?
No. Both forms of ALS (sporadic and familial) occur among people of every ethnicity and race.

Is my family history the key to my risk?
It's not the key, but it is one factor. Almost 90% of cases occur in people who do not have a family history of the disease. Predicting who will get the sporadic form is impossible.

If you have a family history of ALS, figuring out your risk is not easy. Different families have different genes that may make different family members more or less likely to get ALS.

Dominant inheritance. You only need to get one copy to be affected. For example, if one of your parents had ALS caused by a dominant gene, you would have a 50% chance of inheriting the changed gene from that parent.
Recessive inheritance. You need to get one changed gene from each parent to be affected. If you only get one changed gene, you will be a carrier. Carriers do not have the disease; they have one normal copy of the gene and one altered copy. If you're a carrier, one or both of your parents must have been carriers. This also means your brothers and sisters have at least a 50% chance of having inherited the gene from one of your parents.
X-linked inheritance. The X and Y chromosomes make a person male (XY) or female (XX). When a man inherits a change in a gene on the X chromosome, he most likely will be affected by that disease. In the same situation, a woman will be just a carrier because she has a "backup copy" of the gene on her other X chromosome.
Is there a cure?

No. However, people with ALS may benefit from technologies — for example, motorized wheelchairs and electronic communication devices — to compensate for their disabilities.

Related Reading
Amyotrophic Lateral Sclerosis

The Gene For ALS

What goes wrong with this gene?
A handful of genes have been associated with ALS. The best-understood gene is called superoxide dismutase-1 (SOD1). This gene provides the instructions to make a protein called superoxide dismutase. The SOD1 gene is important for the survival of nerves that send electrical signals from the brain to the muscles. Some scientists believe that the lack of SOD1 leaves cells more vulnerable to "programmed cell death," a process used throughout the body to remove cells that are not functioning properly. With this type of "self-destruct" program around, the cell needs some checkpoints to prevent programmed cell death from happening in normal cells. SOD1 could be one of those checkpoints. When you don't have SOD1, nerve cells that should stay alive might be killed off. When the nerves die, the muscles stop working.

Researchers have described more than 100 changes throughout the SOD1 gene. One change is associated with a more rapid progression of the disease, while another change is associated with a slower progression.

Most of the changes in SOD1 cause dominant ALS, meaning you only need to inherit one copy of the change to develop the disease. Changes in SOD1 account for about 20% of inherited ALS cases. Genetic testing is only available for the SOD1 gene. In the other 80% of inherited ALS cases, specific genes have not been found or there is no test available.

Should You Be Tested?

What types of tests are available?
Diagnostic testing
If you have ALS, you can obtain a DNA test to determine whether the disease is caused by a change in the SOD1 gene. Even if you have ALS, your chance of having a change in the SOD1 gene depends on your family history. Remember, most cases of ALS are not related to a change in the SOD1 gene. Work with your doctor to help you decide whether genetic testing makes sense for you.

Pre-symptomatic testing
If you have no symptoms of ALS, a pre-symptomatic test may tell you how likely you are to get the disease in the future. If you have a close family member, such as a parent or a sibling, who has a change in the SOD1 gene, the DNA test can identify whether you share the same change in your SOD1 gene.

Pre-symptomatic testing is controversial because the test cannot determine when you will start having symptoms of ALS or whether you will develop the disease. If you have a change in the SOD1 gene, it does not necessarily mean you will get ALS.

With few exceptions, to qualify for testing you must either have symptoms of the disease or have a close relative (parent or sibling) who has been diagnosed with the disease. Pre-symptomatic testing of children for ALS is typically discouraged. According to generally accepted guidelines for genetic counseling, children under 18 should not be tested for a disease that begins in adulthood unless there is specific benefit to the child.

If you are concerned about your risk for ALS, speak with a medical professional who is knowledgeable about the disease to find out if testing is appropriate for you.

Carrier testing/Prenatal testing
If you have a family history of ALS, carry a change in the SOD1 gene and have a baby on the way, you might want to find out whether your child carries the same change. Even if both you and your future child have a change in the SOD1 gene, it does not mean that either one of you will develop ALS.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

The results of DNA testing for ALS are complicated and rarely provide definitive answers. That's why you should have you results reviewed by a medical professional familiar with the test. He or she can explain how the results apply to you.

What does a positive result mean for me?
If you have symptoms of ALS and test positive for the SOD1 gene, you already know how challenging the disease can be. If you do not have symptoms and you learn that you have inherited the gene for ALS, you might start developing symptoms at about 40 years of age, but it could be many years later. The type of mutation may tell you if the disease is more likely to progress quickly or not, but these predictions are not perfect.

What does a positive result mean for my family?
If you test positive, your brothers, sisters and each of your children have a 50% chance of having inherited the gene. Your brothers and sisters may want to be tested to find out whether they carry the ALS gene. According to generally accepted principles of medical ethics, children under 18 should not be tested for adult diseases such as ALS unless there is an immediate benefit to the child.

Could I get a positive test result, but not carry the disease gene (a "false positive")?
Yes. Sometimes testing uncovers a change in the gene that has not been seen before. When this happens, the laboratory may not know if this change causes the disease or not. Once a new change is seen in several people with ALS, but not seen in healthy people, the laboratory can say that the change causes the disease.

Could I get a negative test result, but actually have the disease (a "false negative")?
Yes. Because more than one gene can cause ALS, not having a change in the SOD1 gene only tells you "there's not a change in your SOD1 gene." You may still get ALS after a negative test because 90% of ALS cases are sporadic.


Personal Questions

How will I cope if the test shows I might develop ALS?
Learning that you are affected by a serious illness is difficult. No formal research has been done on the psychological effects of genetic testing for ALS. Research on people with Huntington's disease, another disorder that gets progressively worse, has shown that people receiving test results tend to accept the news after a period of adjustment.

People who receive negative test results also may need to cope with new feelings. Some report that they feel guilty that they did not get the disease, especially when one of their brothers or sisters was found to carry the gene.

Ultimately, everyone will deal with the information in his or her own way. Most importantly, people who undergo testing should have support available, including friends, family and professional counselors.

If I have the ALS gene, can I have children who don't have the gene?
Yes. If you have the SOD1 gene, you have a 50% chance of passing it on to each child you have.

If I DON'T have the ALS gene, can I have children who DO have the gene?
Yes. If you and your partner do not have a change in the SOD1 gene, then your child cannot inherit the change from you, but it is possible that your child could have a new genetic change that has not been in the family before. Nobody knows exactly how often this happens in the SOD1 gene, but the odds are against it.

Test Details

How does the test work?
The ALS test requires a blood sample. A lab obtains DNA from the blood and looks at the SOD1 gene. If the lab notes any changes from the normal sequence, the test will be reported as "positive."

If you decide to be tested for ALS, you should do it at a medical center that has experience with presymptomatic genetic testing.

If you're thinking about being tested, you probably have a family member with ALS. The neurologist caring for your family member can refer you to a testing center. A center has neurologists, geneticists and counselors with experience in dealing with the complicated issues related to genetic testing. You will have to sign a consent form indicating that you understand and agree to the test.

What do the tests cost?
The test costs about $600. Costs vary slightly depending upon which lab does the testing.

Does insurance pay for the test?
Most health-insurance companies pay 80% or more of the cost of the test. Some companies pay all of the cost, but others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
The results of DNA testing for inherited ALS may take up to three months. The results will not be reported directly to you. Instead, the laboratory provides the results to the medical center that ordered the test. You need to return to the center for another appointment to discuss the results. This way, your family and friends can be there for support when you receive the results.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, though this may depend on whether you have group insurance or are self-employed. Both federal and state laws usually cover people with group insurance, while state laws only cover people who are self-employed. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any "health status-related factor," (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Most states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

Life insurance, long-term care and disability insurance are generally not covered by these laws. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.

Ataxia Telangiectasia Genetic Testing Basics - Medicine and Health

Ataxia Telangiectasia

What is ataxia telangiectasia?
Ataxia telangiectasia (A-T) is a rare but deadly childhood disease that primarily affects the brain and immune system. A-T is a degenerative disease, meaning it gets progressively worse over time. Children with A-T often require a wheelchair by age 10. In the United States, most people with A-T live well beyond 20 years. This is a major change from just a few years ago. Survival for patients in other parts of the world is not as good, perhaps due to lack of good nutrition and therapy.

Symptoms of A-T usually develop in the first 10 years of life, and can include:

Neurological problems, such as a staggering and unsteady pattern of walking, poor coordination, poor balance, slurred speech, uncoordinated eye movements and hearing loss. These develop slowly during childhood as certain nerve cells deteriorate over time.
Skin spots (like birthmarks) or bumps caused by an abnormal pattern of dilated capillaries. They appear as tiny red "spider" veins, commonly on the white part of the eye or on the ears and cheeks.
An increased risk of cancer. About 40% of people with A-T develop some type of cancer in his or her lifetime.
A weakened immune system, which causes frequent infections, such as respiratory infections and pneumonia
Increased sensitivity to X-rays and radiation for cancer treatment. People with A-T and carriers of A-T who receive radiation for cancer treatment should receive lower doses. Other types of radiation, such as CT scans and X-rays, should also be minimized.
Type 2 diabetes can develop in some patients with A-T in their late teens. Type 2 diabetes is the adult-onset form of the disease.
Prematurely gray hair
Difficulty swallowing
Delayed physical and sexual development
Children with A-T usually have normal intelligence.

How common is ataxia telangiectasia
A-T occurs in about 1 of 40,000 live births in the United States. The chance of carrying one change in the gene responsible for the disease is about 1 in 100.

Who is at risk of ataxia telangiectasia?
A-T affects people from all different ethnic groups. People are not at increased risk based on their ethnic background. Someone is typically at increased risk due to his or her family history.

Is there a cure?
No. And there are no standards of treatment. However, there are methods aimed at prolonging survival and improving a person's quality of life:

Antioxidants, such as vitamin E or alpha-lipoic acid, are recommended as a general anti-cancer regimen.
Physical therapy helps to prevent stiff muscles.
Speech therapy may help to maintain communication skills.
Some patients need infusions of gamma globulin (antibodies) to help prevent severe infections.
The Gene For Ataxia Telangiectasia Disease

What goes wrong with this gene?
The gene that causes A-T is called ataxia-telangiectasia mutated (ATM). This gene tells the body how to make an essential protein. If someone inherits two changes (one from mother and one from father) in the ATM gene, the child will not be able to make enough of the ATM protein, which is critical for proper growth and maintenance of the body.

This protein plays an important role in cellular division in the brain during development. If brain cells do not develop correctly, the child will eventually have motor and neurological problems — the very symptoms of A-T.

In addition, the protein acts as a sensor to detect breaks in the DNA. DNA is like a chain of letters. Something like radiation can damage the DNA by breaking that chain of letters, causing a gap between two parts of the chain that are supposed to be connected. Gaps in DNA can cause a change in one of the genes. Normally, when the body notices a break in the DNA, it tells the cell to stop dividing (that is, growing). People with A-T lack this quality-control measure. In fact, telangiectasias (which looks like a birthmark) results when the cells that make capillaries grow out of control. A similar type of abnormal cell growth often leads to cancer in A-T patients.

Should You Be Tested?

What is my risk of being an ataxia-telangiectasia carrier?
Your chances of being a carrier depend on your family history. If someone in your immediate family has A-T or is an A-T carrier, you too could be a carrier. If you have a brother or sister with A-T disease, you have a two-thirds chance of being a carrier. If one of your parents is a carrier, and the other one is not, you have a 50% chance of being a carrier. If your child has A-T disease, it means you and your partner are both carriers of the altered ATM gene.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive as a carrier, what does that mean for my family and me?
If your child has ataxia-telangiectasia disease, you and your partner are both carriers of the altered ATM gene. If you have a close family member with A-T, you might be a carrier. Carriers do not have the full disease; they have one normal copy of the gene and one altered copy. You only need one "working" copy to avoid the full disease. If you're a carrier, one or both of your parents must have been a carrier too. This means your brothers and sisters have at least a 50% chance of having inherited the gene from one of your parents.

Could I get a positive test result, but not carry the disease gene (a "false positive")?
The DNA test for A-T is based on reading the DNA sequence of the gene, and is very specific. If your family includes someone affected by A-T, and this person has a change in the DNA sequence, the lab can look for that same DNA change in you and other family members. In this case, the test will or will not see the same DNA change. There are essentially no false positives.

Sometimes the lab will see a change in the sequence that has never been seen before. It may not be clear if this change causes A-T or not. In this case, they would not tell you that the test is definitely positive, so this would not be a false positive either.

Could I get a negative test result, but actually have the disease (a "false negative")?
False negatives occur in less than 5% of cases tested by sequencing and in about 20% to 25% of cases tested by mutation scanning. This means you could have the disease even though the lab was not able to find a change in the gene. Instead, the disease could be due to a change in an untested part of the gene. In such cases, the lab might be able to use another test called linkage analysis to look for evidence of a genetic change.

Personal Questions

How will I cope if the test shows I am an A-T carrier?
Keep in mind that a carrier does not have the full disease. Carriers, however, may be more sensitive to X-rays and radiation therapy for cancer. It is possible that A-T carriers have an increased risk of developing cancer, but the exact risk is not known. If you are an A-T carrier, each of your children has a 50% chance of inheriting the ATM gene from you.

If I have the A-T gene, can I have children who don't have the gene?
Yes, but you need to "do the math" to understand the risks of passing on the mutated gene.

If you're an A-T carrier and your partner is not, you have a 50% chance of passing the gene to each child. In other words, even if your child inherits your copy of the ATM gene, the child will NOT have A-T, but will be a carrier, like you.

If you and your partner are both A-T carriers, your child has a:

25% chance of inheriting A-T (two copies of the ATM gene)
50% chance of being a carrier (one ATM gene and one normal gene)
25% chance of not being a carrier (two normal genes)
While pregnant, can I determine the risk my baby has of developing ataxia-telangiectasia disease?
To discover whether your unborn child has inherited A-T, you and your partner can seek prenatal testing. Prenatal testing for A-T is only available if you already have a family member with the disease.

The lab looks for changes in the ATM gene in the affected family member. If the affected family member has two identifiable changes in the gene, the lab will look for those same changes in you and your partner. If one or both of you are NOT carriers of these same changes, then your fetus will not inherit A-T from you. If you are both carriers, then your fetus might have the disease, and the lab can look for the same changes in your fetus.

If the affected family member has only one identifiable change in the gene, they must have another change that is undetectable. In this case, your family member would need to have another test called linkage analysis. Linkage analysis can also be used for prenatal testing.

Early in the pregnancy, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab tests the tissue to determine if the fetus has inherited the change in the A-T gene. A baby that inherits only one changed A-T gene will be a carrier. A baby that inherits two changed A-T genes will have the disease.

It's best to plan genetic testing prior to, or early in, the pregnancy. Talk to an obstetrician or a genetic counselor about your options.

If I DON'T have the A-T gene, can I have children who DO have it?
If you're not a carrier, your children cannot inherit the gene from you. They could still get the gene from your partner, if he or she is a carrier, but your children would not get A-T because they would only have one altered gene.

Is there any harm in finding out if I carry the gene?
You may feel upset if you learn that you carry a gene that could potentially cause a disease in your future children.

Test Details

How does the test work?
There are three types of DNA tests for A-T. All require a blood sample, chorionic villus sample or amniotic fluid sample. Testing is used to confirm the presence of A-T in a person who has some or all of the symptoms of the disease, or to test family members to see if they are A-T carriers.

Direct DNA Sequencing
DNA sequencing "reads" the letters of DNA code within the ATM gene. The DNA sequence of any gene is like the ingredients in a recipe. In DNA sequencing, the lab "reads" the sequence to look for typos.

Mutation Scanning
This looks at one letter at a time in the DNA code. Some labs take a shortcut by breaking the gene into pieces and testing each piece for changes. If it looks like a particular piece of the gene carries a change, the lab will examine that piece to find where the change is located. This saves money by not examining the pieces that look normal. The trade-off is that mutation scanning is more likely to miss a change in the gene as compared to sequencing.

Linkage Analysis
Linkage analysis tracks a change in the ATM gene within a family. The test is generally used to detect carriers or for prenatal testing. Typically, you would have linkage analysis done only after someone in your family has been diagnosed with A-T.

The test looks at four representative pieces ("markers") of DNA, two within the ATM gene and two bordering the gene on each side. A lab uses these markers to "find" a change in the gene. For example, imagine a family with one member affected with A-T. While DNA sequencing did not detect a change in the ATM gene, the affected person inherited DNA marker 1. (Family members who do not have A-T have inherited DNA marker 2.) A-T and DNA marker 1 are considered linked because they always go together. Therefore, when testing other members in the same family, the lab will assume a person has a change in the ATM gene if they inherit marker 1 (which is always linked to A-T) and not marker 2 (which is not linked to A-T).

What do the tests cost?
DNA sequencing costs about $4,000. Mutation scanning costs about $1,000. If more than one family member is being tested, the lab will usually charge the full price for the first person and significantly less for each additional person. The cost is highest for the first person because the lab must look at the whole gene. Once the lab finds the changes in the gene for that person, the lab can then look specifically for just those changes in other family members, usually for a cost of about $250 per additional person.

Does insurance pay for the tests?
Most health-insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
The sequencing test takes about two to three months; if the lab has already tested someone in your family the results will arrive sooner. Mutation scanning takes up to four months. The lab sends results to the medical center that ordered the test. You will need to return to the center to learn your results.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, though this may depend on whether or not you have group insurance or are self-employed. People with group insurance are usually covered by both federal and state laws, while people who are self-employed are covered only by state laws. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health-insurance discrimination based on any "health-status-related factor" (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

These laws generally do not cover life insurance, long-term care and disability insurance. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.

Down Syndrome Genetic Testing Basics - Medicine and Health

Down Syndrome

What is Down syndrome?
Down syndrome, a disorder that is present at birth, affects the body's physical and mental development. While no two people with Down syndrome are exactly alike, they do share some common physical features. Babies with Down syndrome have similar facial features, tend to have lower muscle tone, and typically learn to walk and talk slightly later than other children. A person with Down syndrome typically has a slightly small head that is flattened in the back; up-slanted eyes; extra skin folds at the inner corners of the eyes; small ears, nose and mouth; short stature; small hands and feet; and some degree of mental disability.

Normally, a child inherits two copies of chromosome 21 — one from each parent. If a child inherits an extra chromosome 21, the child will have Down syndrome. Because Down syndrome usually affects every cell in the body, people can have a variety of medical problems. For example, about 40% of children with Down syndrome are born with a heart problem. This can range from a very small hole between two heart chambers to a very large hole that requires surgery.

Related Reading
Down Syndrome

How common is Down syndrome?
It occurs in about one of every 800 births. Between 3,000 and 5,000 children with Down syndrome are born each year in the United States.

Who is at risk of having a baby with Down syndrome?
Down syndrome can affect people from any ethnic group. A couple's likelihood of having a baby with Down syndrome increases as the woman gets older. For example, when a woman is 35, Down's occurs in about one of every 200 births. By age 40, Down's occurs in almost one in 100 births. Researchers think older eggs (a woman carries all of her eggs from birth) may have problems sorting out the correct number of chromosomes.

In addition, people have an increased risk if they carry a translocation involving chromosome 21.

Is there a cure?
No, but the medical complications associated with Downs can be treated and managed. Treatment for Down syndrome is specific to an individual's needs. For example, a child or adult may need heart surgery to correct a heart defect. In addition, someone with Downs might need occupational therapy, physical therapy and speech therapy.

The Genes For Down Syndrome

A typical person with Down syndrome has an extra copy of every gene on chromosome 21. This can happen for two reasons:

Unequal Cell Division
An egg begins as a pre-egg cell that has two copies of each chromosome. A pre-egg cell divides into two eggs. Before it divides, the chromosomes are sorted out so that one copy of each chromosome will go into each of the two eggs. When unequal cell division occurs, one egg gets two copies of chromosome 21, and the other egg gets none. When the egg with two copies of chromosome 21 combines with a sperm (which carries one copy of chromosome 21), the baby inherits three copies of the chromosome.

Unequal cell divisions are more likely to occur as a woman ages. (About 10% of the time, the extra chromosome comes from the sperm. This is also due to unequal cell division, but is not clearly related to a man's age.)

Chromosome 21 Translocation
A translocation is a type of chromosomal rearrangement. In one of the parents, for example, one of the two copies of chromosome 21 could break off and combine with another chromosome. All the chromosomes are still present, but in a different order. This parent would have no symptoms of Down syndrome but would be a carrier. The parent could then pass on the remaining, normal chromosome 21 plus the translocated copy, and the other parent would contribute a normal chromosome 21, resulting in a total of three copies of chromosome 21 in the embryo. Therefore, a baby could inherit a regular chromosome 21 from each parent in addition to this rearranged chromosome, resulting in a total of three copies of chromosome 21.

Translocations are not as common, but they increase the risk of having another baby with Down syndrome in a future pregnancy. For that reason, if a baby has Down syndrome caused by a translocation, the parents should have their chromosomes tested.

Should You Be Tested?

Should you have a test for Down syndrome?
Anyone can have a baby with Down syndrome. You might like to know, during the pregnancy, if your baby has Down syndrome. There are two categories of tests:

Screening tests try to identify babies that might have Down syndrome, but these tests cannot tell for sure, they can only tell if your baby is at increased risk of Down syndrome. Screening tests include:

Second trimester (serum) screening (sometimes called a “triple screen” or a “quad screen”) to check for certain substances in the mother's blood
First trimester screening (early ultrasound and serum screening)
Second trimester ultrasound



Diagnostic tests are for women who will be over age 35 at delivery, who received an abnormal result on a screening test, or who are anxious due to a prior pregnancy. Diagnostic tests require a sample of cells from the fetus. Tests include:

Chorionic villus sampling, usually performed between 10 and 12 weeks, involves taking a sample of chorionic villus cells from part of the placenta that contains fetal cells.
Amniocentesis, usually performed after 15 weeks, requires the removal of fetal cells from the amniotic fluid that surrounds the baby.

In both cases, the cells are sent to a lab for analysis.

If you have had a child born with Down syndrome, it is important to have your child's chromosomes checked before starting another pregnancy. If you carry a translocation, you have a higher risk of having another child with Down syndrome.

Be sure to talk with your obstetrician or a genetic counselor about your options.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If my serum screen test or my ultrasound screening test shows an increased risk for Down syndrome, what does that mean for my pregnancy?
It does not mean that your baby will definitely have Down syndrome. You can only confirm whether your child has Down syndrome by receiving one of the diagnostic tests. Talk to your obstetrician or a genetic counselor. They can help you decide whether to pursue a diagnostic test.

Does anyone ever get a positive screening test result and then not have a baby with Down syndrome (a false positive)?
Yes. The serum screen test only indicates that your child will have an increased risk of having Down syndrome. The test produces false positives in 3% to 7% of cases. The early ultrasound can also show false positives. The later ultrasound may frequently show some of the Down syndrome markers in babies without the extra chromosome. Of the three screening tests, the later ultrasound has the highest chance for a false positive.

Does anyone ever get a negative screening test and then have a baby with Down syndrome (a false negative)?
Screening tests are never perfect. The second trimester serum screen and first trimester screening test (early ultrasound with serum screen) detects Down syndrome accurately about 60% to 80% of the time. But if you would like to know for sure, you need a diagnostic test.

Does anyone ever get a positive chromosome analysis and then not have a baby with Down syndrome (a false positive)?
If a baby has an extra chromosome 21 as a fetus, the baby will have Down syndrome.

Rarely, chorionic villus sampling will show an extra chromosome 21 for a baby that does not have Down syndrome. This is a phenomenon called "confined placental mosaicism." Mosaicism means not all the cells of the baby and placenta are the same. The way to figure out if this happened is to have an amniocentesis or periumbilical blood sampling after the chorionic villus sampling to make sure that the cells being tested came from the baby. If the amniocentesis also shows the extra chromosome 21, then your baby will have Down syndrome.

An amniocentesis can verify the results. If the amniocentesis also shows the extra chromosome 21, then your baby will have Down syndrome.

Does anyone ever get a negative chromosome analysis and then have a baby with Down syndrome (a false negative)?
Chromosome analysis detects Down syndrome in more than 99% of cases. While rare, a false negative is possible because a baby can have an extra copy of chromosome 21 in only some cells. That baby would have normal cells and Down syndrome cells. If the chromosome analysis only looks at the normal cells, you could get a false negative.

My doctor said the ultrasound test showed the baby might have Down syndrome. What does that mean?
The ultrasound may show that your child has some of the physical features typical of babies with Down syndrome. Yet, many babies without the disease may have these features. If the ultrasound detects physical features related to Down syndrome in your child, talk to your physician about getting chromosome analysis to confirm the diagnosis.

Personal Questions

My screening test indicates my baby might have Down syndrome. Why should I get an amniocentesis if I'm going to continue the pregnancy no matter what?
A screening test (such as the serum screen or ultrasound) only indicates the increased risk your child has for Down syndrome. If you want to know for sure, you need to receive a diagnostic test (such as amniocentesis). Some couples get tested to lessen their anxiety throughout the rest of the pregnancy. Some couples get tested to help them prepare for the potential birth of a child with Down syndrome. Preparation may include seeking the most suitable hospital for a safe delivery and emotional support.

If I have the Down syndrome translocation, can I have children who don't have Down syndrome?
Yes, depending on which type of translocation you have. One type of translocation makes it so a person can only have children with Down syndrome. With the more common type of translocation, it is possible to have children who do not have Down syndrome. Your risk of having a child with Down syndrome, however, is higher than it is for other people. Further, your children who do not have Down syndrome will fall into two categories — those who carry your same translocation and those who do not. This becomes important if your child decides to start a family.

It is unlikely that both a mother and father would both carry a chromosome 21 translocation. But, if they did, they would have a much higher risk of having a child with Down syndrome.

If I DON'T have the Down syndrome translocation, can I have children who have Down syndrome?
Anyone can have a baby with Down syndrome. If you have a translocation, then your risk is much higher than other people. If you do not have a translocation, then the risk you have, as a couple, depends on the age of the mother.

Is there any harm in finding out if I carry the translocation?
Carrying the translocation for Down syndrome has no known health implications.

If one of my family members has a child with Down syndrome, does that increase my risk?
It depends. If the child does not have a translocation, then your risk is more related to your age at the time of delivery. Consider the example that your sister has a child with Down syndrome. If your sister's child did not have a translocation, then your risk of having a baby with Down syndrome is only related to your age. If your sister's child has Down syndrome caused by a translocation, then you might also carry that translocation. You would need to have your chromosomes examined to know for sure.

Test Details

How do the tests work?
To discover whether your unborn child has inherited Down syndrome, you and your partner can seek prenatal testing. There are two types of tests — screening tests, which identify a fetus that might have Down syndrome, and diagnostic tests, which tell you if the fetus actually does have Down syndrome.

Screening Tests

Second trimester serum screening. This blood test checks the levels of three or four chemicals in the mother's blood during pregnancy weeks 16 to 18. The chemicals are: maternal serum human chorionic gonadotropin (MS-HCG), unconjugated estriol (uE3-estriol), maternal serum alpha-fetoprotein (MS-AFP) and inhibin A (some labs do not test inhibin A). An increase in MS-HCG and inhibin A along with a decrease in the other two markers indicates an increased risk of Down syndrome. The American College of Obstetrics and Gynecology recommends that women under age 35 receive the serum screen test for Down syndrome during their pregnancy.
First trimester screening. This test combines an early ultrasound to measure the thickness of skin at the back of the baby's neck in addition to measuring two markers in the mother’s blood: the free beta subunit of human chorionic gonadotropin ( free beta-hCG), and pregnancy-associated plasma protein-A (PAPP-A). Although this screening test is newer than the second trimester serum screen, it appears to be as effective. A woman can receive an early ultrasound between weeks 11 and 14. Note: because the test requires special ultrasound training, it is not available in all hospitals.
Later ultrasound. This test, routinely performed on all pregnancies at 16 to 20 weeks, involves a detailed survey of the fetal anatomy. This ultrasound is not done specifically to look for Down syndrome, but it may detect features associated with the disorder.

Diagnostic Tests

Chorionic villus sampling. This test collects a small sample of cells from the placenta at the base of the umbilical cord. This is done using a thin needle and ultrasound guidance.
Amniocentesis. This test takes a sample of fluid from around the fetus (without touching the fetus). This fluid contains fetal skin cells.

Both diagnostic tests produce cells containing the fetal chromosomes. These are examined for abnormalities in a lab.

What are the costs of the tests?
The serum screen tests cost about $300 to $400 and the chromosome analysis costs about $1000. Costs for chorionic villus sampling, amniocentesis and ultrasounds vary depending upon the physician and the hospital.

Does insurance pay for the test?
Most health insurance companies pay 80% or more of the cost of these tests. Some plans pay all of the cost, while others won't pay any portion. If you are considering any of these tests, call your insurance company and ask about its coverage.

How long does it take to get results?
Serum screen results take a few days. Ultrasound results are shared on the same day. Chorionic villus sampling and amniocentesis take about two weeks. (Results of these two tests are reported to the medical center that ordered the test. You would then return to the center for another appointment to discuss the results.)

Can a health insurance company raise my rates or drop me from coverage if I have a baby with Down syndrome?
Not usually, although this may depend on whether or not you have group insurance or are self-employed. The Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any "health status-related factor," (including genetic information) by group health plans. People with group insurance are usually covered by HIPAA, while people who are self-employed are only covered by state laws.

Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim.

Duchenne Muscular Dystrophy Genetic Testing Basics - Medicine and Health

Duchenne Muscular Dystrophy

What is Duchenne muscular dystrophy?
Muscular dystrophy refers to a group of disorders characterized by muscle weakness. In Duchenne dystrophy, a defective gene causes muscles to produce abnormally low levels of a protein called dystrophin. When dystrophin levels are low, the membranes around muscle cells become weak and tear easily, eventually leading to the death of muscle fibers.

Duchenne muscular dystrophy is the most common form affecting children, mostly boys. Symptoms usually begin during the toddler years (around ages 2 to 6). The muscle weakness affects many muscles, including those in the trunk and hips. The trunk muscles can become so weak that the spine curves, creating a condition known as scoliosis. Weakness also affects muscles of the arms and legs, the heart muscle and the diaphragm muscle. Children with Duchenne muscular dystrophy will need a wheelchair by the time they are teen-agers. Weakness of the heart muscle, called cardiomyopathy, occurs by age 18 in 100 percent of people with Duchenne muscular dystrophy. Life expectancy depends on how quickly and intensely the disease progresses and on how it affects the ability to breathe. The average lifespan is less than 30 years.

Related Reading
Muscular Dystrophy

How common is Duchenne muscular dystrophy?
About one out of every 3,000 boys is born with the mutation for Duchenne muscular dystrophy. In one-third of cases, a child inherits the gene from his mother. A new mutation in the child accounts for the other two-thirds of cases.

Who is at risk for Duchenne muscular dystrophy?
Every couple has a potential risk of having a boy with Duchenne. No particular group of people has higher rates of being carriers. Family history is the only determining factor.

Is there a cure?
There is no cure for muscular dystrophy, and there are no specifics or standards of treatment. The best treatments prolong survival and improve a person's quality of life. For example:

Physical therapy helps to prevent stiff muscles.
Monitoring for scoliosis allows for early treatment. (Untreated scoliosis can hamper breathing.)
Regular monitoring of the heart (with echocardiograms) allows early detection and treatment of cardiomyopathy.
Attention to diet helps to control the patient's weight.
A type of steroid may help improve muscle strength
The Gene For Duchenne Muscular Dystrophy

What does it mean to have an altered gene for Duchenne?


The gene involved in Duchenne muscular dystrophy tells the body how to make a protein called dystrophin. This protein is important in maintaining healthy muscle cells. Seventy percent of Duchenne muscular dystrophy cases have a large part of the gene missing, which means the muscle cells are unable to make dystrophin. The muscle fibers die, causing the entire muscle to become weak and ineffective.

The Duchenne muscular dystrophy gene is located on the X chromosome. Every male child inherits an X chromosome from his mother and a Y chromosome from his father. Female children get two X chromosomes, one from each parent. If there's a change in an X-chromosome gene, the female has a second X chromosome that almost always carries a normal version of the gene. Males, on the other hand, do not have a second X chromosome. As a result, girls almost never get Duchenne. If a boy has a changed gene, he will automatically get the disease.

Should You Be Tested?

Should you or your future child be tested for Duchenne?
That depends on whether you are a likely to be a carrier of the disease. Your chances of being a Duchenne muscular dystrophy carrier partly depend on your family history. If you are the mother of a boy with this disease and you have another family member with the disease, such as a brother or a nephew, you must be a carrier. If you are the mother of a boy with the disease, but nobody else in your family has it, you still may be a carrier. (About two-thirds of mothers in this situation turn out to be carriers due to the high rate of new mutations.) The only way to learn if you are a carrier is by getting a DNA test. If you are a carrier, you also should have an echocardiogram to look for cardiomyopathy.

Should your child be tested for Duchenne if symptoms exist?
Symptoms of Duchenne muscular dystrophy usually start during the toddler years (ages 2 to 6). An affected child usually will start walking later than expected, have difficulty walking up stairs, walk with flat feet or on the toes. There are different kinds of tests to look for Duchenne. All people with Duchenne muscular dystrophy have high levels of a muscle enzyme called creatine kinase. Therefore, if your child has symptoms of the disease, the first step is the creatine kinase test, as well as some other types of blood tests. DNA testing can be used to confirm a diagnosis in a child who has symptoms.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive as a carrier, what does that mean for my family and me?
A DNA test can confirm that you are a carrier for Duchenne muscular dystrophy. If you are a carrier, you will not have the disease. However, you may have some of the symptoms. The most common symptoms among carriers are muscle weakness and muscle pain or cramping. Note: Cardiomyopathy can affect all Duchenne carriers, so it is important to get an echocardiogram even if you are not experiencing symptoms.

If a DNA change is identified in one family member, then other family members can be tested for the same change. In other words, if you are a carrier and your mother was a carrier, each of your sisters has a 50-percent chance of having inherited the gene. Your sisters may want to be tested before they start families.

If my child tests positive, what does that mean for my family and me?
If your child has symptoms of Duchenne muscular dystrophy, and his creatine kinase is high, your doctor should get a DNA test to confirm the diagnosis. If the child has a Duchenne muscular dystrophy gene, the mother should be tested to see if she is a carrier.

Does anyone ever get a positive test result, but not get the disease (a "false" positive)?
Changes to the Duchenne muscular dystrophy gene can cause two other types of muscular dystrophy. In Becker muscular dystrophy, symptoms start later and progress more slowly. The other type of muscular dystrophy is X-linked dilated cardiomyopathy, which is limited to the heart muscle.

Does anyone ever get a negative test result, but actually have a mutation in the gene (a "false" negative)?
Yes. About 30 percent of people with Duchenne muscular dystrophy will get a negative result with the standard test for deletions. Because the Duchenne muscular dystrophy gene is very large, it has been difficult to test every single part of the gene. A deletion test is done first because it is easier to do. If the deletion test is unsuccessful, your doctor may suggest a different DNA test to look for small changes in the gene. However, even the second DNA test sometimes fails to find any change. But after doing both types of DNA tests, a change will be found in about 90 percent of people with Duchenne muscular dystrophy. This makes the false-negative rate about 10 percent.

When DNA testing fails to detect the Duchenne muscular dystrophy gene in a boy with symptoms of the disease, a muscle biopsy can confirm the diagnosis. A very small piece of the thigh muscle is removed and examined for the presence of the dystrophin protein. A muscle biopsy used to be required to diagnose Duchenne muscular dystrophy, but due to the success of DNA testing, a biopsy is now required in only a minority of cases.

Personal Questions

If I have the Duchenne gene, can I have children who don't have it?
If you're a Duchenne muscular dystrophy carrier, you have a 50-percent chance of passing the gene on to each child you have. Boys who inherit the gene will develop Duchenne muscular dystrophy. All girls who inherit the gene will be carriers.

While I'm pregnant, can I determine the risk my baby has of developing Duchenne?
To discover whether your unborn child has inherited Duchenne muscular dystrophy, you and your partner can get prenatal testing. Prenatal DNA testing is only performed if someone in your family has the gene or is known to be a carrier. Early in the pregnancy, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab then tests the tissue sample to determine if the fetus has inherited the disease.

If you are using in vitro fertilization, you may be able to have the embryo examined right after the egg and sperm are combined and before the resulting embryo is implanted in the womb.

Be sure to talk with your obstetrician or a genetic counselor about your options.

If I am a Duchenne carrier, could I give birth to a girl with the disease?
In rare cases, a girl can get Duchenne muscular dystrophy. However, this only occurs in conjunction with some other problem in the inheritance of the X chromosomes. So, a muscular dystrophy specialist should evaluate any girl with symptoms of Duchenne muscular dystrophy.

If I DON'T have the Duchenne gene, can I have children who DO have the gene?
If you're not a carrier, then your children cannot inherit the gene from you. But there is a relatively high occurrence of new changes in the Duchenne gene. Because of this, there is no guarantee that you won't have a child with Duchenne muscular dystrophy.

Is there any harm in finding out if I carry the gene?
Carrying the gene can cause medical problems for some women. The most significant problem for women who carry a Duchenne muscular dystrophy mutation is dilated cardiomyopathy. A standard echocardiogram can detect this complication. Early detection helps to prevent later complications.

Test Details

How does the test work?
There are two types of DNA tests for Duchenne muscular dystrophy:

Deletion testing looks for large deletions and duplications in the gene. This test reveals the disorder in about 70 percent of patients with Duchenne muscular dystrophy.
Point-mutation testing detects smaller changes than the ones found by the deletion test, such as small insertions, deletions and point mutations.
Some patients with symptoms of Duchenne have a normal point-mutation test. A muscle biopsy will clarify the diagnosis in patients with symptoms, but who have received a normal DNA test. Muscle biopsy also helps when the symptoms are not classical but some type of change is found. The muscle is examined under a microscope and a special stain is used to detect dystrophin protein.

What is the cost of the test?
Cost varies slightly depending upon which lab is doing the testing. The DNA deletion test costs about $500. The DNA point-mutation test costs about $1,100. The special stain for dystrophin in the muscle biopsy costs about $800.

Does insurance pay for the test?
Most health-insurance companies will pay 80 percent or more of the cost of the test. Some companies pay all of the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
Once you have blood drawn for the deletion test, you will receive the results in three to four weeks. Results for the point-mutation test take 12 to 18 weeks. Staining for dystrophin protein in the muscle biopsy takes 1 to 2 weeks. The test results will not be reported directly to you. Instead, the laboratory provides the results to the medical center that ordered the test. You would then return to the center for another appointment to discuss the results.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, although this may depend on whether or not you have group insurance or are self-employed. The Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health-insurance discrimination based on any "health status-related factor," (including genetic information) by group health plans. People with group insurance are usually covered by HIPAA, while people who are self-employed are covered only by state laws.

Hereditary Hemochromatosis Genetic Testing Basics - Medicine and Health

Hereditary Hemochromatosis

What is hereditary hemochromatosis?
Hereditary hemochromatosis is a genetic disorder in which too much iron builds up in the body. The body extracts iron from foods. If you absorb more of this mineral than you get rid of, iron builds up in the tissues and organs. Over time, this buildup can become toxic and cause changes, including:

Liver enlargement, liver cancer, cirrhosis and/or liver failure
Diabetes, from excess iron in the pancreas
Darker skin pigmentation, from iron deposits in the skin
Cardiomyopathy (changes in the heart muscle that prevent part or all of the heart from contracting normally and can lead to heart failure)
Stiff and painful joints
Abdominal pain
(In men) infertility, loss of libido and impotence
Weakness, lethargy and confusion
Related Reading
Hemochromatosis

How common is hereditary hemochromatosis?
In the United States, up to one in 250 white people (Caucasians) carries two copies of the hereditary hemochromatosis gene. About one in 10 people of northern European ancestry (for example, Scottish, Irish or English) is a carrier. Given the high number of carriers, as many as 1 in 150 Caucasians may have two changes in the gene. . Only about half the people with two changes in the gene will develop symptoms. On the other hand, some people with only one detectable change develop symptoms. They probably have another genetic change somewhere, but it doesn't show up on genetic testing. Some cases probably are never diagnosed (that is, they go unreported) because the symptoms and complications of the disease develop so gradually.

Who is at risk of hereditary hemochromatosis?
Hereditary hemochromatosis is more common among Caucasians. African-Americans and Asian Americans could carry the gene, but it is less common.

Because the buildup of high levels of iron in the body is gradual, symptoms normally do not appear until middle age. That's why hereditary hemochromatosis is most commonly diagnosed in men between 40 and 60 and in women after menopause.

Is there a cure?
No, but treatment for hereditary hemochromatosis is 100% effective. High iron levels can be lowered by periodically removing a small amount of blood. Removing blood from the body (a process called phlebotomy) prevents excess iron from being stored in organs and tissues. Treatment is most effective when hereditary hemochromatosis is detected early. Unfortunately, many people do not know they have hereditary hemochromatosis until they develop symptoms. If treatment is started early enough, some symptoms may be reversible or never appear at all. In later stages, symptoms may not be reversible.

The Gene For Hereditary Hemochromatosis

What is the hereditary hemochromatosis gene?
The hereditary hemochromatosis gene helps to regulate the amount of iron absorbed by the body. The gene tells the body how to make a certain protein that is involved in moving and storing iron.

An altered hereditary hemochromatosis gene can change the way the body transports or stores iron, leading to iron overload.

What changes in the gene lead to hereditary hemochromatosis?
The most common changes in the gene are named C282Y and H63D. These names describe the locations of the changes within the gene.

The C282Y change is the most significant. Most people — but not all — who inherit two copies of the C282Y change will develop hereditary hemochromatosis. Up to one-third of people with two C282Y changes do not develop any symptoms.

A person with two H63D changes has less than a 1% chance of developing hereditary hemochromatosis.

A person with one C282Y change and one H63D change has about a 5% chance of developing hereditary hemochromatosis.

How do you get hereditary hemochromatosis?
Every child inherits two hereditary hemochromatosis genes — one from each parent. A child who inherits two altered (mutated) copies of the gene will have an increased risk of hereditary hemochromatosis. A person who inherits an altered gene from only one parent will not develop the disease, but can pass the altered gene on to his or her children.

How does hereditary hemochromatosis develop?
The symptoms you might develop, and when you might develop them, depend on your iron level. The buildup of iron occurs over many years.

In addition to your genetic makeup, other factors affect your body's iron level, and therefore how the altered gene affects your body:

Gender: Men have a higher risk of developing hereditary hemochromatosis (women do not build up iron as quickly as men do because women lose iron-rich blood through menstruation and pregnancy).
Diet: People take in different amounts of iron in their diets.
Alcohol intake: Drinking too much alcohol can accelerate the buildup of iron.
Should You Be Tested?

Should you have a test for hereditary hemochromatosis?
Many doctors believe all adults should be screened for hemochromatosis by a transferrin saturation test. That way, people at risk could get early treatment. DNA testing makes the most sense if you have a family history of the disease, or if you are experiencing symptoms.

Should I be tested if I have no signs of hereditary hemochromatosis?
If you have a family history of hereditary hemochromatosis, you might want to find out if you could be a carrier or are susceptible to getting hemochromatosis. If a family member has already tested positive for one or two changes in the gene, your risk of carrying an altered gene is increased. If you don't have any signs of hereditary hemochromatosis and a test determines that you have an increased risk of the disease, you could take action now to help prevent some of the consequences of the disease (or stop it from developing altogether). Talk with your doctor about getting your iron levels checked. If they are high, then you might need treatment.

If I don't have a family history of the disease, should I be tested?
If you do not have a family history of hereditary hemochromatosis, your chances of being a carrier depend on your family's ethnic background. The C282Y and H63D changes are most common in people with ancestors from northern, western and central Europe. Because the medical community has not established clear guidelines for testing based on ethnic background alone, talk to your doctor about your options. Most doctors would not recommend a gene test unless you or one of your relatives have a high iron level.

What does family history tell me?
If you have a family member with hereditary hemochromatosis, you might be a carrier (have one altered gene) or you might have the disease (have two altered genes). Most people with two copies of the C282Y change eventually develop hereditary hemochromatosis. However, up to one-third of people with two C282Y changes will not develop the disease.

Should I be tested if I have symptoms of hereditary hemochromatosis?
Testing can confirm whether someone with symptoms of hereditary hemochromatosis has the disease. If you have symptoms, see your doctor. Symptoms are most obvious late in the disease. By then, treatment is less effective. Tell your doctor if you have a family history of hereditary hemochromatosis or if your ethnic background is European. Based on this information, your doctor can decide which test is right for you.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive, what does that mean for my family and me?
There are three tests for hereditary hemochromatosis: transferrin saturation, ferritin and DNA.

If your transferrin saturation or ferritin levels are high, you may have hereditary hemochromatosis. Because hemochromatosis refers to any type of iron overload, your doctor will need to investigate the cause of your condition. Other conditions, such as inflammation and cancer, can cause a high ferritin level.

To determine if you have hereditary hemochromatosis you will need DNA testing. A positive DNA test means you have changes in the hereditary hemochromatosis gene. Symptoms of hereditary hemochromatosis occur in:

About 3% or fewer of people with only one change (C282Y or H63D)
About 5% of people with one C282Y gene and one H63D gene
About 1% of people with two H63D changes
The majority of people with two C282Y changes
It's hard to predict who will develop symptoms of hereditary hemochromatosis, even with DNA testing. That does not mean testing has no purpose. DNA testing helps identify people who should have their iron levels checked regularly. DNA testing also helps to decide who needs a liver biopsy. People with two C282Y changes and a high iron level should have a liver biopsy to look for cirrhosis. Most importantly, testing helps people seek treatment before any damage begins.

If a DNA test reveals that you have two changes, it means your parents are both carriers of the altered gene. Carriers do not typically have the disease, because they have one normal copy of the gene as well as one altered copy. If both your parents are carriers, your brothers and sisters each have a 25% chance of inheriting two altered genes.

If you are a carrier, it means one or both of your parents must have been a carrier, too. This means your brothers and sisters have at least a 50% chance of having inherited one altered gene from one of your parents.

Once a change is identified in a person, other family members might want to be screened by DNA testing.

Could I get a positive test result, but not have hereditary hemochromatosis (a "false positive")?
The transferrin saturation test can be falsely elevated if you did not fast before the test.

If you were fasting, getting a false-positive result depends on the "cut-off" value used for the test. Cut-off levels range from 45% to 62%. Recommendations to make 45% the cut-off are designed to detect as many true positives as possible. If your value is higher than 45%, the possibility of hereditary hemochromatosis increases. If the cut-off were 50%, there would be fewer false positives, but testing would also miss some people with hereditary hemochromatosis.

Choosing cut-off values is difficult because the percent saturation that reliably indicates hereditary hemochromatosis will vary with diet, age and gender.

The ferritin test could be elevated from another illness that causes inflammation, or from some types of cancer.

The false-positive rate is essentially zero for the DNA test. In other words, if the DNA test is positive, a change has been detected in your hereditary hemochromatosis gene. However, whether or not that change will likely lead to hereditary hemochromatosis depends on which specific change you have and on other factors such as gender and dietary habits.

Could I get a negative test result, but actually have the disease (a "false negative")?
A false negative for the transferrin saturation test depends on the cut-off value. If the cut-off were 50% saturation, then people with hereditary hemochromatosis who had values from 45% to 50% would get negative test results even though they have the disease. Based on previous studies of people with two hereditary hemochromatosis gene changes, a cut-off value of 45% detected 100% of men with hereditary hemochromatosis but only 91% of women with the condition.

Because iron builds up gradually in people with hereditary hemochromatosis, a person with the genetic change could have a normal ferritin level. For example, younger people with one or two changes in the gene have not had enough time to build up high levels of iron. Ferritin testing is not recommended for hemochromatosis screening because up to half of people with two C282Y changes will have a normal ferritin – a high false negative rate!

The false-negative rate is very low for the DNA test. If you have one of the known changes, the test will find it more than 99% of the time.

Note: Detecting changes in the hereditary hemochromatosis gene explains most cases of hereditary hemochromatosis, but some cases appear to be caused by a different gene.

Personal Questions

What if the DNA test shows I am a hereditary hemochromatosis carrier?
If you inherit a defective gene from only one parent, you are considered a carrier of the disease. Your chances of actually developing hereditary hemochromatosis are 5% or less. That's because hereditary hemochromatosis is usually inherited as a recessive disease: You need two altered genes, rather than one, to have symptoms.

If you have two C282Y changes, get your ferritin level checked yearly. If the level is high, your doctor will routinely remove some iron by taking out a portion of your blood. This process will continue until you get down to a normal ferritin level.

Some combinations of genes cause the disease in only a small percentage of people with those combinations. For example, what should you do if you have the combination C282Y and H63D? Or what if you have only one change, but there have been some people with that change who developed hereditary hemochromatosis? In both cases, you should get your transferrin saturation checked periodically. (Your doctor can help you to decide how often.) The goal is to detect iron storage problems before any damage is done.

If I have a change in the hereditary hemochromatosis gene, can I have children who don't have the change?
Yes, but you need to "do the math" to understand the risks of passing on the change in the gene. If you have one copy of the gene and your partner has two normal genes, you have a 50% chance of passing the altered gene to each child. If you and your partner both have an altered hereditary hemochromatosis gene, your child has a:

25% chance of inheriting two altered copies of the gene
50% chance of inheriting one altered copy and 1 normal copy
25% chance of inheriting two normal copies of the gene
Even with these risks, being a carrier would not stand in the way of having children. In fact, knowing that you and your partner are carriers of the gene could make your children healthier. Because the carrier rate is so high in the Caucasian population, there are plenty of children born with hereditary hemochromatosis who don't know it until they become adults and get some symptoms. Knowing your carrier status would allow your children to receive earlier screening and treatment as a result of that knowledge.

During pregnancy, can I determine the risk my baby has of developing hereditary hemochromatosis?
In theory, prenatal testing is available for any type of DNA test, but it would be very unusual to have prenatal testing for a disease like hereditary hemochromatosis. The disease has no effects for years and doesn't need treatment until adulthood. But if you decide to have the test, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab then tests the tissue to determine if the fetus has inherited a change.

If I DON'T have a change in the hereditary hemochromatosis gene, can I have children who DO have a change in the gene?
If you do not carry an altered gene, your children cannot inherit the gene from you. They could still get the gene from your partner if he or she is a carrier.

If my partner or I have a change in the hereditary hemochromatosis gene, should my children be tested?
Hereditary hemochromatosis is an adult disease. There is no need to test a child. Even with two altered genes, nothing would be done until your child becomes an adult. Although there are no specific guidelines, it would be reasonable for your child to be tested with either the transferrin saturation test or the DNA test after turning 18.

Test Details

How do the tests work?
There are three types of tests for hereditary hemochromatosis. All require a blood sample:

Transferrin Saturation Test
Transferrin saturation testing determines whether your iron level is too high.

Iron moves around your body by attaching itself to different molecules. Transferrin grabs iron and moves it from one place to another. The higher your transferrin saturation, the higher your iron level.

With the transferrin test, a lab measures the iron level in your blood and the percentage of transferrin molecules that are NOT bound to iron. The lab uses those two values to estimate the percentage of transferrin that is bound to iron. When a binding site is occupied by iron, it is saturated. Typically, this test is done before a DNA test.

Ferritin Test
Transferrin saturation testing determines whether your iron level is too high. Ferritin is a protein in your blood that contains iron. Saying that your ferritin level is high is another way of saying that your body is storing too much iron. This test works well for monitoring people who already know they have a change in the gene. For example, the level can be checked before and after treatment. It’s not such a good test for screening people who don’t know if they have a change in the gene.

DNA Test
The DNA test looks for changes in the hereditary hemochromatosis gene. The test specifically looks for the most common changes: C282Y, H63D and S65C (another common change in the gene, but one that has not been shown to cause any hemochromatosis symptoms).

The DNA test is important because two people with hereditary hemochromatosis might not have the same change in the gene. Depending on your DNA test results, your doctor might choose to follow your iron levels more or less frequently.

What do the tests cost?
The transferrin saturation test and ferritin test each cost about $75. The DNA test costs about $200. Costs vary depending on the lab doing the testing. Note: Screening family members with the DNA test has been shown to be more cost effective than screening with the transferrin saturation test.

Does insurance pay for these tests?
Most health-insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
You should receive the results of the transferrin saturation test within a day or two. The DNA test takes about two or three weeks. The laboratory sends the results to the medical center that ordered the test. You should have a return appointment to discuss your results.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, although this may depend on whether or not you have group insurance or are self-employed. Both federal and state laws usually cover people with group insurance, while state laws only cover people who are self-employed. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health-insurance discrimination based on any "health status-related factor" (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Many states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

These laws generally do not cover life insurance, long-term care and disability insurance. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.

Huntington's Disease Genetic Testing Basics - Medicine and Health

Huntington's Disease

What is Huntington's disease?
Huntington's disease is an inherited disease that affects nerve cells in parts of the brain. A progressive disease (meaning it continues to get worse), Huntington's leads to mental deterioration and the loss of control over the body's muscle movements.

Symptoms usually start in the late 30's or early 40's. Some people have symptoms earlier or later. Once symptoms begin, they continue to get worse. Ultimately, the disease leads to premature death, typically 15 to 20 years after the first symptoms appear.

Different symptoms appear at different stages of the disease:

Early Stages — mental difficulties, poor coordination, possibly some involuntary movements.

Later Stages — a movement disorder called chorea (a "dancing" type of movement that involves uncontrollable jerking of the arms and legs). Muscles, such as those that control speech and swallowing, may become impaired.

Long Term — mental abilities (memory, comprehension, concentration, etc.) gradually worsen. Individuals may have outbursts of aggressive behavior or other psychiatric symptoms, including depression and paranoia. Worsening symptoms render Huntington's patients less able to perform jobs and regular daily activities.

Related Reading
Huntington's Disease

How common is Huntington's disease?
Huntington's affects between three and seven Caucasians out of 100,000. In the United States, that equals about 9,000 to 21,000 people. The disease appears to be less common in other ethnic groups, such as Chinese, Japanese and African blacks.

Compared to some other diseases, Huntington's is rare. Multiple sclerosis, for example, affects between five and 10 times more people in the United States than Huntington's. Schizophrenia affects 1,000 people per 100,000 (or about 3 million people in the U.S.).

Who is at risk of Huntington's disease?
Huntington's disease is not caused by an infection or by exposure to a toxin in the environment. The disease is caused by a genetic change (an alteration). You only need to inherit one copy of the altered gene to be affected. You get one copy of a gene from your mother and one from your father. If either parent has Huntington's, you have a 50 percent chance of getting the altered gene.

If neither of your parents have Huntington's disease (and they are at the age when people normally start showing symptoms), you probably have nothing to worry about. But keep a few things in mind. Some people with the altered gene do not develop symptoms until several years after the usual age when symptoms begin. Also, a parent who might have eventually developed Huntington's disease might have died from another cause before showing any symptoms of the disease. Because of these exceptions, you may not be able to easily tell whether or not you are at risk.

If you have concerns about yourself or family members being affected, tell your doctor. Your doctor can direct you to a genetic counselor.

Is there a cure?
No. Huntington's disease cannot be cured.

Before you consider getting a genetic test to learn if you have inherited an altered gene for Huntington's disease, imagine how you might feel if you discovered that you would develop a debilitating disease with no cure. If you decide to get tested, talk to a medical professional (such as a genetic counselor) to help you deal with the implications of the test results.

The Gene For Huntington's Disease

What does it mean to have an altered gene for Huntington's?
A gene is like a recipe. In the case of Huntington's disease, part of the gene is "expanded," causing it to be defective. Imagine if the phrase "add 1 teaspoon of salt" appeared fifty times in a recipe. That much salt would ruin whatever you were making.

In general, the number of repeats in the "recipe" of a gene is associated with the severity of the disease. With more repeats, the disease starts at an earlier age. This relationship is not perfect, so people with the Huntington's gene won't know exactly when they will start to show symptoms.

Should You Be Tested?

What are my chances of getting Huntington's?
This depends on your family history. With few exceptions, in order to qualify for testing, you must either have symptoms of the disease or have a close relative (a parent or sibling) who has been diagnosed with the disease. If you have no family history of the disease and you don't have any symptoms, you are not likely to have the altered gene.

Note: You may not have all the facts about your family history available. For example, if some members of your family died at an early age, you might not know the cause of death. And some families don't like to talk about their disease history.

If you are concerned about Huntington's disease, talk to a knowledgeable medical professional, such as a genetic counselor, to find out whether testing is right for you.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive for Huntington's, what does that mean for my family and me?
If you don't have symptoms now, but you inherited the gene for Huntington's disease, you might start having symptoms at about age 40. If you have already experienced some of the symptoms, you know how challenging this disease can be.

Because the disease starts later in life, many people who decide to get a genetic test for Huntington's disease already have children. If you test positive, it means your brothers, sisters, and each of your children have a 50 percent chance of having inherited the gene. Your brothers and sisters may want to be tested as well.

According to generally accepted principles of medical ethics, children under 18 should not be tested. A positive test result creates a lot of worry for someone so young. Because there is no treatment for Huntington's disease, the test does not need to be done right away. It's better to wait until a child turns 18 so he or she can make an independent decision about whether to learn if they have the gene for Huntington's.

Does anyone ever get a positive test result, but not have the disease (a "false" positive)?
No. The test measures the number of abnormal DNA repeats in the gene. If there are too many repeats, the test result is positive. The test is extremely accurate in counting repeats, so it is unlikely that a positive result would be incorrect.

Does anyone ever get a negative test result, but actually have the disease (a "false" negative?)
If you receive a negative test result, you can be confident that you will not develop the disease. If a change is present, the test will find the change in the gene 98 percent of the time.

Personal Questions

How will I deal with it if the test shows I'm going to develop Huntington's disease?
Learning that you are affected by a serious illness is obviously difficult. Research on the psychological effects of genetic testing for Huntington's disease has shown that people receiving the test results tend to accept the news after a period of adjustment.

Only about 20 percent of eligible people take the test. Perhaps only people who are ready to deal with the information want to get the test. Also, because only a qualified center can perform the test, people being tested receive extra support to help them deal with the results.

Finally, it's not only the people who get positive test results who have trouble adjusting. People who receive a negative test result have reported feeling guilty that they did not get the disease, especially when one of their brothers or sisters was found to carry the gene. Everyone will deal with the information in his or her own way.

Ultimately, you should make sure you have the support of friends, family and professional counselors prepared to help you deal with these issues.

If I have the Huntington's disease gene, can I have children who don't have it?
Yes. If you have the Huntington's disease gene, you have a 50 percent chance of passing it on to each of your children. If you find out if you have the gene prior to becoming pregnant, or early in the pregnancy, you can have prenatal testing to find out if the fetus is affected. If you want prenatal testing, your obstetrician can tell you about how those tests are done and how the results might affect a pregnancy.


If I don't have the Huntington's disease gene, my children won't have it, right?
This is a tricky question. Think of the gene like a recipe. If you have too many repeats of one "ingredient," you will get the disease. But if you have only slightly more repeats than normal, you will not develop Huntington's. However, the number of DNA repeats in the gene can increase when being passed from a parent to a child at the time of conception. With enough of an increase, your child will develop Huntington's disease. This is more of an issue for someone who gets a test result that's in between the normal number of repeats and the number associated with the disease. If nobody in your family has Huntington's, you shouldn't start worrying about your children getting the disease.

Is there any harm in finding out if I have the gene?
Although it is stressful to receive positive test results, most people respond well once they are given time to adjust to the news. The rate of suicide is not dramatically higher among people taking the test as compared to the general population.

The period of adjustment will be, of course, different for different people. For this reason, testing is done through a medical professional who can provide the necessary support to a person struggling to accept this difficult news.

Test Details

How does the test work?
If you decide to be tested for Huntington's, you need to enroll with a medical center that has a formal protocol for predictive genetic testing. If you're thinking about being tested, you probably have a family member with Huntington's. The neurologist caring for your family member often can refer you to a testing center. Testing centers have neurologists, medical geneticists and genetic counselors with expertise to help you face the complicated issues related to predictive testing.

Before you receive the test, you will have to sign a consent form indicating that you understand and agree to the test. The test usually requires taking about 1 teaspoon of blood from your arm and sending it to a lab that does testing. A lab obtains DNA from the blood sample and uses special techniques to determine the number of repeats in the gene.

If there are a low number of repeats, the result is reported as "negative" or "normal."

If there are a large number of repeats, the result is reported as "positive" or "abnormal."

An in-between number of repeats is more difficult to interpret because these people could be unaffected, but are still able to have children with an abnormal number of repeats.

If the test result is positive, however, that means the lab is very sure that there are enough repeats to cause the disease.

How much does the test cost?
The test costs approximately $300. Costs vary slightly depending on what lab does the testing.

Does insurance pay for the test?
Most health-insurance companies will pay 80 percent or more of the cost of the test. Some companies pay all of the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.

How long does it take to get results?
Once you have blood taken for the test, you will receive your results in two to three weeks. Test results will not be reported directly from the laboratory to you. Instead, the laboratory provides the results directly to the medical center that ordered the test. You would then return to the center for another appointment to discuss the results. This way, family and friends can be there to support you when you hear the news.

Can a health-insurance company raise my rates or drop me from coverage if I test positive?
Not usually, though this may depend on whether you have group insurance or are self-employed. Both federal and state laws usually cover people with group insurance, while state laws only cover people who are self-employed. Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any "health status-related factor," (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. More than half the states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

Life insurance, long-term care and disability insurance are generally not covered by these laws. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.

Phenylketonuria Genetic Testing Basics - Medicine and Health

Phenylketonuria

What is phenylketonuria (PKU)?
Phenylalanine is an amino acid found in protein-rich foods such as meats and dairy products. People with phenylketonuria lack the enzyme needed to break down this amino acid, which leads to a toxic buildup of phenylalanine in their bodies.

PKU has both a genetic and an environmental component. While the disease starts with a genetic problem — the lack of a critical enzyme — it's actually the presence of phenylalanine in someone's diet that causes symptoms. The main signs and symptoms include:

Severe mental retardation
Small head size (microcephaly)
Seizures
Behavior problems
The disorder is most harmful if it goes undetected during a child's early development (from birth to 6 months). High levels of phenylalanine disrupt brain development. Before newborn screening for PKU began, PKU was a common cause of mental retardation. Today, newborn screening is offered in all 50 states. By identifying babies with PKU right after they are born, treatment can begin before high levels of phenylalanine can cause brain damage.

Related Reading
Phenylketonuria

How common is phenylketonuria?
Phenylketonuria affects about one in 15,000 newborns in the United States.

Who is at risk of phenylketonuria?
Your highest risk of having a child with PKU comes if you have already had a child with phenylketonuria. Unfortunately, most people don't know they are carriers when they start having children. PKU affects people from a wide range of ethnic groups. Among people with European or Chinese ancestors, the incidence varies from about one in 10,000 to one in 15,000 live births. PKU is less common among people with an African-American or Latino background. Among people from some Arabic-speaking countries the incidence may be as high as 1 in 3,000. The incidence is lowest among people with Japanese ancestry; about one in 140,000 live births.

Is there a cure?
No, but the disease can be effectively managed. For newborns and infants with phenylketonuria, strict control of phenylalanine levels in their diets helps them to avoid mental retardation and seizures associated with untreated PKU. Babies with PKU are given special formulas that contain other amino acids (the building blocks of protein), but not phenylalanine.

Children and adults with PKU need to limit their protein intake and carefully monitor their phenylalanine levels on a regular basis. Decreasing the amount of protein-rich foods can decrease phenylalanine levels to a safe range. Because a low-protein diet is not healthy, people with PKU rely on special protein formulas.

The Gene For Phenylketonuria

What goes wrong with this gene?
The gene that causes phenylketonuria is called phenylalanine hydroxylase (PAH). This gene tells the body how to make the PAH enzyme. This enzyme converts phenylalanine into another amino acid.

If you inherit two changes in the PAH gene, one from your mother and one from your father, you will not be able to make enough of the enzyme to convert phenylalanine into another amino acid. In turn, this causes increased levels — toxic levels — of phenylalanine in your body.

Should You Be Tested?

What is the risk of being a phenylketonuria carrier?
The chance that you or your child is a carrier depends on your family history. If someone in your immediate family (parent, brother, sister) has phenylketonuria or is a PKU carrier, you also could be a carrier. If one parent is a carrier, and the other is not, you have a 50% chance of being a carrier. If you have a brother or sister with PKU, then both your parents must be carriers, and you have a two-thirds chance of being a carrier.

Your future child's risk of being a carrier depends on whether you and your partner are carriers. If one of you is a carrier, each child will have a 50% chance of being a carrier. If both of you are carriers, each of your unborn children has a 25% chance of having PKU. The chance that your unaffected children will be carriers is two-thirds.

Should I consider prenatal testing?
To discover whether your unborn child has inherited phenylketonuria, you and your partner can seek prenatal testing. Prenatal testing is generally only available if you already have a child with PKU. The lab will look for changes in that child's PAH gene. If there are two identifiable changes in the gene, the lab will then look for those changes in you and your partner. Because each of you is a carrier, each of you should have one of the changes. The lab can look for the same changes in your fetus.

If your affected child has only one identifiable change in the gene, he or she must have another change that is undetectable. In this case, your family would need to have a DNA test called linkage analysis, which also can be performed for prenatal testing. Linkage analysis takes a lot of time, so you must plan this out before becoming pregnant.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

What does a positive prenatal screening test mean for me and my child?
If your future child has two changes in the PAH gene, he or she will have phenylketonuria. Your doctor will need to test the newborn's phenylalanine level and begin treatment with low phenylalanine formula.

What does a positive newborn screening test mean for me and my child?
If your newborn child tests positive for phenylketonuria, he or she may have PKU. Screening tests are not foolproof, so your child will need follow-up testing to confirm a diagnosis. If your child does have PKU, he or she should be referred immediately to a doctor with expertise in amino acid disorders.

Could my child get a positive newborn screening result, but not have phenylketonuria (a false positive)?
Yes. False positives occur because the test is designed to be very sensitive in detecting elevated phenylalanine levels. If your child receives a positive screening test, he or she will need another test to confirm the high phenylalanine level. If the level remains high, your child may have phenylketonuria or some other form of high phenylalanine. The other forms of high phenylalanine are also caused by changes in the PAH gene, but the symptoms are much milder than PKU.

Could my child get a negative newborn screening result, but have phenylketonuria (a false negative)?
Yes, but the false negative rate is extremely low. The newborn screening looks at the level of phenylalanine in the baby's blood. Phenylalanine comes from protein, so the baby will not have any detectable change in the phenylalanine level until protein is consumed. Babies get protein from breast milk or infant formula. The more protein they eat, the higher the phenylalanine level. A false negative can come about if a baby is tested before eating enough protein. This means the baby has phenylketonuria, but simply has not consumed enough protein for the level of phenylalanine to be high.

Undetected cases of PKU may have extremely damaging results. If a baby with PKU does not receive special low-phenylalanine formula in the few days after birth, his or her phenylalanine levels will rise, leading to brain damage and other problems associated with untreated PKU.

If I test positive as a carrier, what does that mean for me and my family?
If your child has phenylketonuria, you and your partner are both carriers of the altered PAH gene. Carriers do not have PKU. They have one normal copy of the gene and one altered copy. You only need one normal or "working" copy of the gene to avoid the full disease. If you're a carrier, one or both of your parents must have been carriers, too. This means your brothers and sisters have at least a 50% chance of having inherited the gene from one of your parents.

Could I get a positive carrier test result, but not carry the disease gene (a false positive)?
Rarely, but it depends on the type of test used.

Carrier testing based on the parent's amino acid levels may produce false positives depending on the time of day and the type of food eaten, or a woman’s menstrual cycle. This type of carrier test is not accurate during pregnancy. If done correctly, the chance of a false positive is 1% or less.

Some labs test for carriers by using a DNA test or DNA sequencing to detect common changes in the gene. If your affected family member has one of these changes, the test will find whether you have it as well. There are essentially no false positives with this type of testing.

Even if you know you are a carrier because you have a child with phenylketonuria, a carrier test might not find the change. The disease could be due to a change in an untested part of the gene. To counter this, labs use another DNA test (called linkage analysis) to look for evidence of a genetic change. The false positive rate is less than 1% for this test.

Could I get a negative carrier test result, but actually carry the disease gene (a false negative)?
Rarely, but it depends on the type of test used.

Carrier testing based on the parent's amino acid level may produce false negatives. The time of day you received the test and what you have eaten prior to the test may affect the results. When the test is done under the right circumstances, the chance of a false negative is 1% or less.

While the PAH gene has more than 400 changes, many labs check only the most common changes in the gene. This test is best for when someone in your family is already known to have one of the common gene changes. In such a case, there would be essentially no false negatives when testing other family members.

DNA sequencing of the entire gene produces a low rate of false negatives — about 1% — when used on everybody with phenylketonuria. False negatives occur when someone has a DNA change that is close to, but not in, the gene. If someone in your family already has a known change in the gene, then the sequencing test will be able to find that change in other family members with essentially no false negatives.

Personal Questions

What does it mean if the test shows I am a phenylketonuria carrier?
Carriers of a phenylketonuria gene change do not develop symptoms or have any health problems related to being a carrier. The main issue is the risk of having children who are either PKU carriers or who actually have PKU.

If I carry the phenylketonuria gene, can I have children who don't have the gene?
Yes, but you need to "do the math" to understand the risks of passing on the mutated gene. If you're a phenylketonuria carrier and your partner is not, you have a 50% chance of passing the gene to each child. Even if your child inherits your copy of the PAH gene, the child will not have PKU, but simply be a carrier, like you.

If you and your partner are both PKU carriers, your child has a:

25% chance of inheriting PKU (two copies of the PAH gene)
50% chance of being a carrier (one PAH gene and one normal gene)
25% chance of not being a carrier (two normal genes)
If I have phenylketonuria, how does it affect my children?
If you are a woman with phenylketonuria, your child can be affected even if your partner is not a carrier. Children of women with PKU can suffer serious problems, such as mental retardation and heart defects, if the mother's phenylalanine levels are even slightly high during pregnancy. Your child can develop problems even if he or she did not inherit two copies of the gene for PKU.

So, if you're a woman with PKU and are planning a pregnancy, talk to a doctor experienced with PKU before you become pregnant. You will need to monitor your phenylalanine levels closely during the entire pregnancy to ensure the health of your baby.

If I DON'T have the phenylketonuria gene, can I have children who DO have the gene?
If you are not a carrier, your children cannot inherit the gene from you. Because there is no national screening program for phenylketonuria, most people don't know they are carriers unless they have a relative with PKU. Your children could still get the gene from your partner if he or she is a carrier, but the child would not get phenylketonuria because he or she would only inherit one altered gene.

Is there any harm in finding out if I carry the gene?
Just being a carrier of the gene doesn't put you at any health risk. However, you may feel upset or guilty knowing that you carry a gene that could potentially cause a disease in your future children.

Test Details

How do the tests work?


Prenatal Screening Test
Early in the pregnancy, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab then tests the tissue to determine if the fetus has inherited the changes in the phenylketonuria gene. A baby who inherits only one change in the PKU gene will be a carrier. A baby who inherits two changes will have phenylketonuria.

Talk with your obstetrician or a genetic counselor about your options.

Newborn Screening Test
A standard screening test for newborns measures the level of phenylalanine in their blood. Before your baby goes home from the hospital, a nurse will prick the child's heel to obtain a few drops of blood for testing.

Carrier Screening by Amino Acids
The same labs that test the phenylalanine level for children with phenylketonuria also test parents to determine whether they have high phenylalanine levels. The lab also tests the levels of a related amino acid called tyrosine. The levels of these amino acids can vary depending on time of day and diet, so the test is always done before noon after eating a normal breakfast. This test is not accurate during pregnancy.

Carrier Screening by DNA
Some labs examine up to 15 common changes in the gene, but there are more than 400 changes known for this gene. If your child has phenylketonuria, but you don't have one of these changes, you must have a change somewhere else in the gene.

This is the best test when other DNA testing doesn't find a change. The test reads the parts of the gene that provide direct information about how to make the PAH enzyme.

Linkage Analysis
When other tests do not detect a change in the gene, linkage analysis is the only option. This test is not done "up front" because it is more costly and time-consuming.

Linkage testing is done on a blood sample. It looks at DNA markers that are located right near the PAH gene. For example, say you knew a family that had several people affected by phenylketonuria, but the affected people do not have a detectable change in the PAH gene. All the affected people in the family inherited the same DNA marker (marker 1) while all the unaffected people in the family inherited a different DNA marker (marker 2). The disease and marker 1 are linked. When testing other people in the same family, the lab will assume a person has the disease gene if they inherit marker 1.

These markers may be different for each family, so this type of testing can only be done after someone in the family has been diagnosed with PKU.

What do the tests cost?
Each state pays for the costs of its newborn screening program.

Testing outside the newborn screening program varies by type of test. Biochemical testing for phenylalanine level costs about $50. The DNA mutation panel costs about $200 to $300. DNA sequencing costs about $800. The linkage test costs about $300 per person, but the child and both parents need to be tested, so the total cost per family would be about $900. The price for linkage testing does not include the initial cost of finding the change in the person with phenylketonuria. Costs vary slightly from one lab to another.

Does insurance pay for these tests?
Most health insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering any of the carrier tests, call your insurance company and ask about its coverage.

Each state pays for the costs of its newborn screening program, but the state does not pay for screening of the relatives or any other carrier testing.

How long does it take to get results?
Amino acid test results are usually available in a few days. DNA test results typically take two to three weeks, but may be available faster for prenatal testing. The lab sends results to the medical center that ordered the test. You need to return to the center to learn your results.

Can a health insurance company raise my rates or drop me from coverage if I test positive?
Not usually, though this may depend on whether or not you have group insurance or are self-employed. People with group insurance are usually covered by both federal and state laws, while people who are self-employed are covered only by state laws. Also, the federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health-insurance discrimination based on any "health status-related factor" (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

Life insurance, long-term care and disability insurance are generally not covered by these laws. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.