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.

Sickle Cell Genetic Testing Basics - Medicine and Health

Sickle-Cell Disease

What is sickle-cell disease?
Red blood cells are normally round, like a bagel. A genetic change (called a mutation) can make red blood cells more likely to become "sickle" shaped, like a crescent moon. These abnormally shaped cells cause the symptoms and complications of sickle-cell disease.

Round red blood cells are just the right size to squeeze through tiny blood vessels throughout the body called capillaries. Sickle-shaped cells get stuck in these passageways, and even in larger blood vessels, causing problems with the flow of blood. Abnormal cells also don't carry oxygen well. As oxygen in the blood goes down, more cells become abnormally shaped and the problem gets worse. Sickle-shaped cells are also fragile and tend to break apart. This leads to a lower red blood cell count, also known as anemia. That's why sickle-cell disease is often called "sickle-cell anemia."

Sickle-shaped red blood cells are "weeded out" by the spleen, an organ that filters and stores blood and helps to fight infections. Over time, the spleen gets "clogged up" with sickle-shaped cells and stops working. Because children are more susceptible to the types of infections that the spleen normally fights, children with sickle-cell disease take an antibiotic every day for protection. But infection is only one of many complications of sickle-cell disease occurring in the first two years of life. Early diagnosis of sickle-cell disease can help to prevent early complications. Screening programs are the only way to identify people with sickle-cell disease early enough to make a difference.

Those who suffer from sickle-cell disease experience painful episodes or attacks. Episodes can be mild or severe. In more severe attacks, life-threatening problems can occur, such as a stroke or breathing problems due to fluid in the lungs. Potential complications include:

Anemia
Blood clots (thrombosis)
Pain in various parts of the body, especially the joints
Stroke
Eye problems (proliferative retinopathy)
Infections, such as pneumonia
Fluid in the lungs during severe attacks
Enlarged heart or heart murmur
Liver problems, such as jaundice and gallstones
Blockage of the spleen/loss of spleen function
Kidney damage
Painful erections (priapism)
Bone problems (osteomyelitis and avascular necrosis)
Leg ulcers
Delayed growth
Related Reading
Sickle-Cell Anemia

How common is sickle-cell disease?
In the United States, sickle-cell disease affects about one in 650 African-Americans and about half as many Latin Americans. About 8 percent of African-Americans are sickle-cell carriers.

In some parts of Africa, 25 percent of newborn babies carry a sickle-cell disease gene. Why? Having one sickle-cell gene protects against malaria. In areas where malaria is more common, there are more sickle-cell carriers.

Who is at risk of sickle-cell disease?
Sickle-cell disease is very common among people from Africa, including African-Americans. It is most common in West Africa. Sickle-cell disease also occurs in Mediterranean countries, some parts of the Middle East, central India and some Latin American countries. Although it is uncommon, a Caucasian person could have sickle-cell disease.

Is there a cure?
No. Symptoms can be treated with blood transfusions and medications such as hydroxyurea. Painful episodes are less likely to occur if you avoid becoming dehydrated and over-exerted. You should also avoid extreme hot or cold temperatures. Even with excellent medical care, life expectancy is shortened for people with sickle-cell disease.

A bone-marrow transplant can give a person with sickle-cell disease the ability to make normal red blood cells. But the transplantation process is complicated and comes with many risks. This procedure is used only to treat people with very severe complications of sickle-cell disease, and only when a fully matched sibling is available as a donor. Newer approaches to transplantation might allow more people to get this type of treatment in the future.

The Gene For Sickle-Cell Disease

What goes wrong with this gene?
Hemoglobin is the part of the red blood cell that attaches to oxygen and carries it through the bloodstream. Hemoglobin is made of a combination of proteins called globin proteins. Hemoglobin normally contains alpha- and beta-globins.

The beta-globin gene tells the body how to make beta-globin protein. A person with sickle-cell disease has a change (or mutation) in the beta-globin gene. The change in the gene causes the body to make beta-globin protein incorrectly. When the altered beta-globin is used to make hemoglobin it causes the hemoglobin to change to a sickle shape, and this shape leads to the symptoms and complications of sickle-cell disease.

The most common change in the beta-globin gene causes an altered hemoglobin molecule, called hemoglobin S. If you inherit two genes that produce hemoglobin S, you have hemoglobin SS disease, which is the typical form of sickle-cell disease.

The other common change in the beta-globin gene causes the gene to produce hemoglobin C. This altered form of hemoglobin can also form a sickle shape. If you inherit one gene making hemoglobin S and the other one making hemoglobin C, you have hemoglobin SC disease. This is a slightly milder form of sickle-cell disease, but it still causes a lot of problems. Having two hemoglobin C mutations is uncommon and causes a very mild type of anemia.

There are a few other, less common, changes in the beta-globin gene. If any one of these less common changes combines with the hemoglobin S change, it usually results in a milder form of sickle-cell disease.

Should You Be Tested?

What is my risk of being a sickle-cell-disease carrier?
Your chances of being a carrier depend on your family history and your family's ethnic background. If someone in your immediate family has sickle-cell disease or sickle-cell trait, you could be a carrier. Sickle cell trait is the common term for a sickle cell carrier. If you have a brother or sister with sickle-cell disease, there's a two-thirds chance that you are a carrier. If one of your parents is a carrier, meaning they have sickle cell trait, and the other one is not, you have a 50-percent chance of being a carrier.

You also have a higher chance of being a carrier if your ancestors are from a part of the world where sickle-cell disease is common. These areas include: Africa (especially West Africa), Mediterranean countries, some parts of the Middle East, central India and some Latin American countries. It is possible for someone to carry a gene for sickle cell even if their ancestors are not from one of these areas, but it is less likely.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

If I test positive, what does that mean for me and my family?
If your child has sickle-cell disease, you and your partner are both carriers of the altered beta-globin gene. Carriers do not have the disease; they have one normal copy of the gene and one altered copy. You only need one "working" copy to avoid having symptoms. 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-percent 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)?
Both tests — hemoglobin electrophoresis test and DNA test — are very specific. These tests only tell you there is a problem if there really is one. There are essentially no false positives.

Could I get a negative test result, but actually have the disease (a "false" negative)?
The hemoglobin electrophoresis will find anybody who has a sickle-cell gene. The DNA test for sickle-cell disease detects more than 99 percent of carriers. If you took either test, you would have less than a 1 percent chance of receiving a false negative.

Personal Questions

How will I cope if the test shows I am a sickle-cell carrier?
A carrier does not have sickle-cell disease. Carriers seem to live normal lifespans, and only get symptoms of sickle cell under very unusual conditions involving low oxygen or severe dehydration. Carriers should avoid flying in un-pressurized aircraft or getting very dehydrated. The most significant effect of being a sickle-cell carrier is that your children could inherit the sickle-cell gene from you.

If I have the sickle-cell 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 sickle-cell carrier and your partner is not, you have a 50-percent chance of passing the gene to each child. Even if your child inherits your copy of the sickle-cell gene, the child will NOT have sickle cell, but simply be a carrier, like you.

If you and your partner are both sickle-cell carriers, your child has a:

25-percent chance of inheriting sickle cell (two copies of the sickle-cell gene)
50-percent chance of being a carrier (one sickle-cell gene and one normal gene)
25-percent chance of not being a carrier (two normal genes)
During pregnancy, can I determine the risk my baby has for developing sickle-cell disease?
To discover whether your unborn child has inherited sickle cell, you and your partner can seek prenatal testing. The first step is to be tested to find out if you and your partner are both sickle-cell carriers. If one or both of you are NOT carriers, then your baby will not have sickle-cell disease. If you are both carriers, then your baby might have the disease.

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 change in the beta-globin gene. A baby that inherits only one changed beta-globin gene will be a carrier. A baby that inherits two changed beta-globin genes will have sickle-cell disease.

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

If I DON'T have the sickle-cell gene, can I have children who DO have the gene?
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 they would not get sickle-cell disease because they would only have one altered gene.

Is there any harm in finding out if I carry the gene?
Carrying the gene has no significant health implications. You may, however, 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 two types of tests for sickle cell. Both require a blood sample.

Hemoglobin Electrophoresis Test
The hemoglobin electrophoresis test can tell you if you have normal hemoglobin (called hemoglobin A) or one of the hemoglobin variants: S or C. It can even tell you if you have some of each, which happens in people who are sickle-cell carriers. Most states use this test on all newborn babies to see if they have sickle-cell disease.

DNA
This test can be done as a prenatal test on tissue from a chorionic villus sampling or amniocentesis. It can also be done on blood from the parents. The DNA test looks for a change in the beta-globin gene. The test looks at the two common changes for hemoglobin S and hemoglobin C.

What does the test cost?
The hemoglobin test costs about $75. The DNA test costs about $300. Costs vary depending upon the lab.

Does insurance pay for the test?
Most health-insurance companies pay 80 percent 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?
Hemoglobin results should be available in a few days. DNA test results usually 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.

Tay-Sachs Genetic Testing Basics - Medicine and Health

Tay-Sachs Disease
What is Tay-Sachs disease?
Tay-Sachs is a very rare disease of the nervous system. Symptoms usually start during infancy or in early childhood, and become progressively worse over time. People with Tay-Sachs have a mutation in a gene that makes an important enzyme called hexosaminidase A (or HEXA for short). This altered gene causes waste material to build up in nerve cells, which damages the cells. Different mutations cause different effects on enzyme activity. The amount of remaining enzyme activity dictates the severity of disease. With lower enzyme activity, the waste builds up faster. The damage leads to problems of the nervous system, such as seizures and the loss of vision. There are three common forms of Tay-Sachs disease:

Infantile
Infants with Tay-Sachs appear normal at birth. They live without problems until they are about 6 months old. The first symptoms usually include muscle weakness and some muscle twitching. Loud noises may startle an infant with Tay-Sachs more than you might expect, causing the baby to cry. As these infants grow, they are less able to perform normal activities for their age and they become less interactive. Infants may develop seizures and experience vision loss by the end of their first year. They become deaf and unable to swallow, and their muscles weaken, eventually leading to paralysis. Most do not survive beyond the toddler years.
Juvenile
A less severe form of Tay-Sachs starts during childhood (usually between ages 2 and 10). Children with this type of disease can develop normally through their toddler years. As young children, however, they start to develop problems with body coordination and the muscles that control speech. As in the case of infants with Tay Sachs, these children also may develop seizures and vision problems. Unfortunately, although the symptoms might come later than those of infantile Tay-Sachs and some children survive into their teen years, death usually occurs in the late teen years.
Chronic and Adult-Onset
Much rarer than infantile Tay-Sachs, the chronic and adult-onset forms of the disease start later and develop more slowly. These forms are associated with numerous neurological problems, such as poor coordination, movement disorders, speech problems and sometimes mental illness. Because the buildup of waste material in brain cells is more gradual, the brain's ability to function may be preserved for many years.
Related Reading
Tay-Sachs Disease

How common is Tay-Sachs disease?
Tay-Sachs is very rare. Each year, about a dozen cases of Tay-Sachs are diagnosed in the United States, most of the infantile form. Tay-Sachs can affect people from any ethnic group, but people whose ancestors are Ashkenazi Jews have the highest likelihood of being carriers. Jewish leaders have made a point of educating people about the risks. Before this education started in the 1970s, Tay-Sachs affected about one in 3,600 children of Ashkenazi Jewish descent. Today, the rate has gone down in this group by more than 90 percent. In fact, it is now more common for the parents of a child with Tay-Sachs to be non-Jewish.

About 3 percent of people of Ashkenazi Jewish descent carry the Tay-Sachs gene. Some non-Jewish groups of people have high carrier rates, including people whose ancestors were French-Canadian, from the Louisiana bayou, or from Amish populations in Pennsylvania.

Who is at risk for Tay-Sachs disease?
Tay-Sachs disease is a result of changes in the hexosaminidase A gene (HEXA). Every child inherits two HEXA genes — one from each parent. If a child inherits one normal gene and one altered gene, the child will not develop Tay-Sachs because the one normal gene is enough to avoid the buildup of waste in the cells. (This child will be a carrier of the altered gene, however, and can pass the gene on to his or her children.)

If the child inherits two altered copies of the HEXA gene — one from each parent — the child will get Tay-Sachs disease.

It is very unusual for two people to be Tay-Sachs carriers if neither parent is of Ashkenazi Jewish descent or from another high-risk group. If you're not in one of these high-risk groups, it's not likely that your doctor would offer you the test.

Is there a cure?
No. Tay-Sachs is a progressive disease without a cure.

The Gene For Tay-Sachs Disease
What goes wrong with this gene?
The gene for Tay-Sachs disease tells the body how to make a protein (enzyme) called hexosaminidase A. When the amount of this enzyme is decreased, or when the enzyme is not working properly, waste products build up inside the body's cells. This causes damage to organs such as the liver, eyes and brain.

Changes happen in different parts of the HEXA gene. Changes in one part can cause the enzyme to be totally shut off. Changes in another part might only cause a decrease in the amount of enzyme made. Other changes can cause a poorly functioning enzyme. This explains why some people get the severe form of the disease (from having no enzyme) while some get the later-onset forms (because they have some enzyme, but not enough to break down all of the waste products).

In other words, there is a threshold. If you are below it, you can't compensate for the waste. If you're above it (like a carrier) you won't get the disease.

Should You Be Tested?
Is my ethnic background the key to my risk?
Your chances of being a Tay-Sachs carrier depend on your family's ethnic background. The American College of Obstetrics and Gynecology recommends a test called an enzyme-activity test, used to detect Tay-Sachs carriers, if one or both partners are of Ashkenazi Jewish descent. If only one partner is of Ashkenazi Jewish descent, that person should be tested first. You should also consider screening if you are in another high-risk group such as French-Canadian, Cajun or Amish. If you're pregnant, you and your partner can choose to be tested at once to learn if you might be passing along the HEXA gene.

Understanding Test Results and Options
How Do You Make Sense Of The Results?
If I test positive, what does that mean for me and my family?
Tay-Sachs testing can confirm a diagnosis in a child who has symptoms of the disease or test whether a person who has no symptoms is a carrier.

The first step is the enzyme-activity test. Lower enzyme activity usually means a person has worse symptoms. Infants with the disease tend to have no enzyme activity at all. People with the juvenile and chronic forms of Tay-Sachs tend to have low enzyme activity.

If enzyme activity is low, the DNA test can help determine the exact change in the gene. If a DNA mutation is identified in one family member, then other family members can be screened by DNA testing. Otherwise, they should be screened by the enzyme-activity test.

If your biological child has Tay-Sachs, you and your partner are both carriers of the altered HEXA gene. Carriers do not have the disease; they have one normal copy of the gene and one altered copy. You only need one "working" copy to have the enzyme activity you need. 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-percent 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)?
This is a tricky question. Some people may have a Tay-Sachs mutation called "pseudo-deficiency," a fancy way of saying, "it looks like your enzyme isn't working, but it really is."

Enzyme activity is about 50 percent of normal in Tay-Sachs carriers. For people with pseudo-deficiency, enzyme activity is lower. In the case of infantile Tay-Sachs, the enzyme activity is often zero. This can happen because mutations in one part of the gene can make an enzyme that's totally inactive (true deficiency). Other mutations make a weak enzyme that's still effective enough that you don't get the disease (pseudo-deficiency).

This is one reason why a test that shows low enzyme activity is followed by a DNA test. If the DNA test shows you have the pseudo-deficiency, you would not have an affected child. This is true even if your partner carries the Tay-Sachs mutation. People who have one nonworking gene plus one pseudo-deficiency gene have lived into their 60s without having any symptoms.

Could I get a negative test result, but actually have the disease (a false negative)?
The enzyme activity test for Tay-Sachs detects about 97 percent of carriers. If you took the test, you would have, at most, a 3 percent chance of receiving a false negative result.

The DNA test has a higher chance of missing someone who either has the disease or is a carrier. The DNA test only recognizes the most common mutations in the HEXA gene; it does not recognize every possible mutation. For example, certain mutations are more common among people of Ashkenazi Jewish descent. The DNA test detects about 92 percent of Tay-Sachs carriers among people of Ashkenazi Jewish descent, but is less effective for other individuals.

Personal Questions
How will I cope if the test shows I am a Tay-Sachs carrier?
Simply being a carrier has no impact on your health. Your children, however, could inherit the Tay-Sachs gene.

If I have the Tay-Sachs 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 Tay-Sachs carrier and your partner is not, you have a 50-percent chance of passing the gene to each child. Even if your child inherits your copy of the Tay-Sachs gene, the child will NOT have Tay-Sachs, but simply will be a carrier, like you.

If you and your partner are both Tay-Sachs carriers, your child has a:

25-percent chance of inheriting Tay-Sachs (two copies of the Tay-Sachs gene)
50-percent chance of being a carrier (one Tay-Sachs gene and one normal gene)
25-percent chance of not being a carrier (two normal genes)
Someone with the chronic or adult-onset form of the disease may have children. Since a person with Tay-Sachs has an alteration in both copies of their HEXA gene, their children would have a 100-percent chance of receiving a Tay-Sachs gene. However, whether or not the child gets the disease will depend on the other parent. If the other parent was a Tay-Sachs carrier, the child would have a 50-percent chance of inheriting the disease.

Of more than 90 HEXA mutations known, more than 70 are associated with the infantile form of Tay-Sachs. There are also several mutations associated with the chronic form.

During pregnancy, can I determine the risk my baby has of developing Tay-Sachs?
To discover whether your unborn child has inherited Tay-Sachs, you and your partner can seek 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 then tests the tissue to determine if the fetus has inherited the disease.

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

If I DON'T have the Tay-Sachs gene, can I have children who DO have the gene?
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 they would not get Tay-Sachs disease because they would only have one altered gene.

Is there any harm in finding out if I carry the gene?
Carrying the gene has no health implications. You may, however, 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 two types of tests for Tay-Sachs. Both require a blood sample:

Enzyme activity
The enzyme-activity test checks how well the HEXA enzyme is working. Anyone with Tay-Sachs symptoms or who wants to know if he or she is a possible carrier should start with the enzyme test. If this test comes back normal, you're not a carrier (with about 97 percent certainty). If the activity test is abnormal, you will need to get the DNA test.
DNA
The DNA test is important because two people with a HEXA mutation might not have the same gene mutation. More than 90 different mutations of the HEXA gene exist. Most mutations cause the severe form of Tay-Sachs, but some cause the later-onset forms or the pseudo-deficiency. For routine testing, most commercial labs only do the DNA test for the six most common mutations. If you only get the DNA test, and you have one of the less common mutations, you will get a false negative. The less common mutations still cause a decrease in enzyme activity, so they show up on the enzyme-activity test. If your enzyme test was abnormal, then your doctor can ask the lab to look for the less common mutations.
What does the test cost?
The enzyme activity test costs about $130. The DNA test costs about $225. Costs vary depending upon the lab doing the testing.

Does insurance pay for the test?
Most health-insurance companies pay 80 percent 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?
Once you have blood drawn, you will receive results in two to three weeks. The laboratory sends the 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 my 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 only covered 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.

How Do You Make Sense Of The Results - Medicine and Health

If I am the mother of a child who has a full mutation in the fragile X gene, does that mean I'm a carrier?
Yes. Every mother of a child with a full mutation in the FMR1 gene is a carrier of a repeat at the pre-mutation or full mutation level.

If I test positive as a carrier, what does that mean for me?
A man or a woman who carries a fragile X pre-mutation will generally have normal intellectual abilities and a normal appearance, but a carrier of an FMR1 repeat is at risk of having some symptoms of fragile X syndrome. For example, among pre-mutation carriers:

21% of females experience premature ovarian failure (which can lead to infertility and a lack of normal female hormones).
Some older men develop tremors and an unsteady gait. This is known as fragile X Tremor-Ataxia Syndrome. Some people develop a mild learning disability. This would be someone with normal intelligence who has problems in a certain area, such as math or reading. They may need extra help in school.
How does being a fragile X carrier affect my family?
A woman who is a fragile X pre-mutation carrier has a 50% chance of passing the gene on to her children. When the gene is passed on, the number of repeats in the gene could stay the same or could increase.

A man who is a pre-mutation carrier has a 100% chance of passing the gene on to his daughters (because they always get his X chromosome) and no chance of passing the gene on to his sons (because they always get his Y chromosome, never his X). It is rare for the number of repeats to increase significantly when passed down from the father.

If the number of repeats stays the same, the child will be a pre-mutation carrier. If the number of repeats increases to more than 200, the child will have a full mutation. A boy who inherits a full mutation will have fragile X. A girl who inherits a full mutation will have fragile X about half of the time, but her symptoms will typically be milder.

Family members of a carrier are also at risk of having fragile X syndrome or passing it on to their future children.

For men:

If your father was a pre-mutation carrier, you cannot inherit the gene from him because the father only gives his X chromosome to his daughters.
If your mother was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier (if you are not already affected).
If your daughter had a child with fragile X syndrome, you are almost certainly a pre-mutation carrier and at risk for developing fragile X Tremor-Ataxia Syndrome, the symptoms of which are tremors and an unsteady gait.
For women:

If your father was a pre-mutation carrier, you have inherited his affected gene. It is rare for the number of repeats to increase when passed down from the father, so you will most likely be a pre-mutation carrier also.
If your mother was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier (if you are not already affected).
If your sister was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier.
Could I get a positive test result, but not carry the disease gene (a false positive)?
The test for fragile X is highly accurate for the full mutation. False positives for a full mutation are unlikely. If the number of repeats ranges between intermediate and pre-mutation, it may be difficult to determine whether someone is a carrier. Each case must be interpreted individually.

Could I get a negative test result, but have a change in the gene that I could pass on to my children (a false negative)?


False-negative test results can occur if:

Only one DNA testing method (polymerase chain reaction [PCR] or Southern Blot) is used. On rare occasions, a person may appear to have a normal number of repeats according to the PCR test when they actually have an abnormal gene. The Southern blot test, however, will find the abnormal gene.
The number of repeats lies in the intermediate range. A lab cannot always provide a guaranteed interpretation for results that fall in the "gray zone" between normal

The Gene For Fragile X Syndrome - Medicine and Health

What is the fragile X gene?
The gene responsible for fragile X syndrome is called Fragile X Mental Retardation-1 (FMR1). The FMR1 gene tells the body how to make a protein called Fragile X Mental Retardation Protein (FMRP). Although scientists are still trying to understand its exact function, the FMRP protein is important to the health of nerve cells in the brain.

What goes wrong with the fragile X gene?
A gene is like a recipe for making a protein. The DNA molecules that make up a gene are like the words in a recipe. In one part of the fragile X gene, three "letters" are repeated several times. A few repeats of this sequence doesn't cause a problem, any more than adding a few extra dashes of salt to a recipe would ruin it. Too many repeats, however, creates havoc when a cell tries to "read the recipe." Imagine reading a cake recipe and you see, "add 1 teaspoon of salt" repeated 50 times. Clearly, a cake with that much salt will not taste right. Likewise, repeating a DNA sequence many times over will cause problems.

How does the change happen? The number of repeats can increase if the gene is passed from parent to child. The body makes a copy of each gene before it is passed on. Changes also can occur when the gene is being copied.

How is the change in the fragile X gene passed along?
The FMR1 gene is on the X chromosome. Males inherit one X chromosome from the mother and one Y chromosome from the father. Females get two X chromosomes, one from each parent. If there is a change in an X chromosome gene that could cause a problem, girls have a second X chromosome that almost always carries a normal version of the gene. Boys, on the other hand, do not have a second X chromosome to fall back on. As a result, a boy with too many repeats in the FMR1 gene will get the disease. About half of girls with too many repeats in the FMR1 gene are mentally retarded, but their symptoms are often milder than those of boys.

What are the four classes of fragile X repeats?


Normal: A normal number of repeats ranges from about five to about 40. Within this range, the number of repeats stays the same when the gene is passed on to a child. The child would not have fragile X.
Intermediate: Between 41 and 58 repeats is a "gray zone." Fragile X genes in this range are less stable. When the gene is passed on, the number of repeats may increase, but usually not enough to cause a problem. The child would not have fragile X.
Pre-mutation: When the number of repeats ranges from about 59 to about 200, the gene is in a state of "pre-mutation." The child would not have fragile X, but the number of repeats could increase when the gene is passed on to the child. A female who carries a fragile X gene of this size is at higher risk for premature ovarian failure.
Full mutation: When the number of repeats is greater than 200, the gene cannot work properly. A boy who has a fragile X gene with more than 200 repeats will have fragile X syndrome. A girl with more than 200 repeats may have fragile X, but often with milder symptoms. More than 99% of people with fragile X carry a full mutation. The other 1% probably have another change in the same gene that can’t be detected by routine genetic testing.
Are gene repeats the only change in the gene?
No. There is another change associated with the repeats. When the number of repeats is greater than 200, the gene almost always has another change, called methylation. This means that a chemical group, called a "methyl group," is attached to the gene. With a methyl group attached, the gene cannot work. If the gene is not working in a boy, he will have fragile X. If a girl's FMR1 gene is methylated, she may have fragile X syndrome or she may be protected by a normal FMR1 gene on her other X chromosome.

Methylation causes the most severe symptoms. Knowing the methylation status of the gene helps predict how severe fragile X syndrome will be for a particular person.

A small number of people with fragile X syndrome — less than 1% — do not have a large number of repeats or methylation in the gene. These people have something else wrong with the gene. Routine DNA testing only looks at the number of repeats and methylation. Testing for less common fragile X mutations is offered at a limited number of labs.

Who is at risk of fragile X syndrome - Medicine and Health

Family history is the key to determining your risk of fragile X syndrome. Women who are carriers are at risk of having children with fragile X. Men who are carriers are at risk of having children who are also carriers. Fragile X can affect people from any ethnic group.