AMINO ACID DISORDER

Disorder name: Homocystinuria
Acronym: CBS
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• What is homocystinuria?
• What causes homocystinuria?
• If homocystinuria is not treated, what problems occur?
• What is the treatment for homocystinuria?
• What happens when homocystinuria is treated?
• What causes the CBS enzyme to be absent or not working correctly?
• How is homocystinuria inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have homocystinuria or be carriers?
• Can other family members be tested?
• How many people have homocystinuria?
• Does homocystinuria happen more often in a certain ethnic group?
• Does homocystinuria go by any other names?
• Where can I find more information?

This fact sheet contains general information about homocystinuria. Every child is different and some of these facts may not apply to your child specifically. Certain treatments may be recommended for some children but not others. Children with this condition should be followed by a metabolic doctor in addition to their primary care provider.

WHAT IS HOMOCYSTINURIA?

It is one type of amino acid disorder. People with this condition have problems breaking down an amino acid called methionine from the food they eat.

Amino Acid Disorders: Amino acid disorders (AAs)These are a group of rare inherited conditions. People with amino acid disorders cannot digest particular amino acids – the building blocks of protein. These amino acids, along with other toxic substances, build up in the body. This can cause serious effects on health, growth, and learning. are a group of rare inheritedAcquiring a trait from one’s parents. Most traits, such as eye color or hair color, are inherited from a parent through genes. conditions. They are caused by enzymesA molecule that helps chemical reactions take place. For example, enzymes in the stomach speed up the process of breaking down food. Each enzyme can participate in many chemical reactions without changing or being used up. that do not work properly. ProteinA molecule that makes up many parts of every cell in the body. Examples of proteins include hormones, enzymes, hair, and antibodies. Proteins are made up of 20 different types of individual units called amino acids. It is the order of these amino acids in a protein that determines what form and function a protein has. Each gene holds the instructions for making a single protein. is made up of smaller building blocks called amino acidsAmino acids are small molecules that make up proteins. There are over 100 different amino acids, but our body uses only 20 amino acids to make all of its proteins. Our genes determine the sequence of amino acids in a protein. This sequence determines what shape the protein takes, and what function that protein serves in the body.. A number of different enzymes are needed to process these amino acids for use by the body. Because of missing or non-working enzymes, people with amino acid disorders cannot process certain amino acids. These amino acids, along with other toxic substances, then build up in the body and cause problems. The symptoms and treatment vary between different amino acid disorders. They can also vary from person to person with the same amino acid disorder. See the fact sheets for each specific amino acid disorder. Amino acid disorders are inherited in an autosomal recessive manner and affect both males and females.

WHAT CAUSES HOMOCYSTINURIA?

In order for the body to use protein from the food we eat, it is broken down into smaller parts called amino acids. Special enzymes then make changes to the amino acids so the body can use them.

Homocystinuria is caused by problems with the enzyme “cystathionine beta-synthase” (CBS). In people with homocystinuria, CBS is either missing or not working properly. This enzyme’s job is to break down methionineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein.. When the CBS enzyme is not working correctly, methionine and another amino acid, homocystineThis is a type of amino acid made by the body. High levels can occur in people with homocystinuria or certain other metabolic disorders., build up in the blood and cause problems.

IF HOMOCYSTINURIA IS NOT TREATED, WHAT PROBLEMS OCCUR?

Babies with homocystinuria look healthy and normal at birth. Over time, if the condition is not treated, it can cause growth and learning delays. It can also affect the eyes, bones, heart, and blood vessels.

There are two types of homocystinuria. The milder type can be treated with vitamin B6 supplements. The other type does not respond to vitamin B6This is a type of B vitamin. It is also called pyridoxine. It helps in the breakdown and use of food for energy. It is found in beans, meat, fortified cereal, and some fruits and vegetables. It can also be bought in pill form. Vitamin B6 supplements are sometimes given to people with homocystinuria.. Symptoms of both types vary widely from person to person.

Growth, learning, and behavior
Delays in growth and learning are often noticed between the ages of one and three. Common effects in untreated children include:

• poor growth
• problems gaining weight
• delays in crawling, walking, and talking
• behavior and emotional problems
• serious learning disabilities or intellectual disabilities

Eyes
Children usually start to develop vision problems after one year of age. They develop severe nearsightedness and have trouble seeing objects that are far and not close to them. If this is not treated, the lens of the eye can become loose and move out of place. This is called “lens dislocationThis is a condition in which the lens of the eye becomes loose and moves out of place. If it is not treated, it can lead to a serious eye condition called glaucoma. This can lead to blindness if left untreated..” This often happens between two and eight years of age. GlaucomaThis is a serious eye condition. It causes increased pressure of the eyeball. If it is not treated, it can damage the nerve to the eye and cause blindness. If detected and treated in time, blindness can be prevented. Glaucoma is the second leading cause of blindness in the United States., a condition caused by increased eye pressure, can happen over time if the lens dislocation is not treated. Untreated glaucoma can cause blindness.

Bones and skeleton
Teens and adults are often very tall and slender. They may have very long arms, legs, and fingers. By the teen-age years, about half have thinning of the bones, called osteoporosisThis is a condition that causes the bones to become thinner over time. People with this condition have a higher chance for bone fractures..

Muscle weakness, especially in the legs, is a problem for some children.

Heart and blood vessels
If not treated, homocystinuria can cause blot clots resulting in heart disease or strokeThis is when the blood or oxygen supply to part of the brain is stopped. It can be caused either by a blood clot or a leak in a blood vessel. A stroke may cause loss of speech and language and the ability to move certain body parts. If severe, it can cause death.. In fact, stroke and heart disease are the main causes of early death in people with untreated homocystinuria.

Other
Children who are not treated often have pale hair and skin. Some will have episodes of pancreatitis that causes severe pain, and some may have seizuresThese are also called "convulsions" or "fits." During a seizure, a person loses consciousness and control of his or her muscles. It may also cause involuntary movements. Seizures can happen for many reasons. Some causes are metabolic disorders, a metabolic crisis, brain injury, and infection.. Some individuals may develop psychiatric conditions including anxiety, depression, obsessive-compulsive behavior, and psychotic episodes.

WHAT IS THE TREATMENT FOR HOMOCYSTINURIA?

Your baby’s primary doctor will work with a metabolic doctorThis is a doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They often work in university hospitals or large medical centers. and a dietician to care for your child.

Prompt treatment is needed to prevent intellectual disabilities and other serious health problems. Most children need to eat a special diet low in methionine, drink a special formula, and take supplements every day. You should start the treatment as soon as you know your child has this condition. Lifelong treatment is usually needed to prevent or control the symptoms.

The following are treatments often recommended for children with homocystinuria:

1. Low-methionine diet
The special diet is made up of foods that are very low in methionine which is found in protein. This means your child must eat a diet low in protein and avoid high protein foods such as cow’s milk, regular formula, meat, fish, cheese, or eggs. Regular flour, dried beans, nuts, and peanut butter also contain methionine and must be avoided or strictly limited.

Many vegetables and fruits have only small amounts of methionine and can be eaten in carefully measured amounts. There are other medical foods such as special low-protein
or low-methionine flours, breads, and pastas that are made especially for people with homocystinuria.

Your metabolic doctor and dieticianThis is a person with special training in food and nutrition. A registered dietician (RD) has met the necessary educational requirements and has passed a national examination. If your child has a metabolic disorder, it is important for you to work with a registered dietician. They help create healthy food plans for people with metabolic disorders or other special needs. will decide on the best food plan for your child.  Your child’s diet will depend on many things such as his or her age, weight, and blood test results. Your dietician will fine-tune your child’s diet over time. The diet is usually needed throughout life.

2. Medical Foods and Formula
In addition to a low-methionine diet, some children are given a special medical formula as a substitute for milk. This formula will give your child the correct amount of nutrients and protein while helping to keep his or her methionine and homocystine levels within a safe range. Your metabolic doctor and dietician will tell you what type of formula is best for your child and how much to use.

Some states offer help with payment for this special formula and others require private insurance coverage for formula and other special medical foods.

3. Supplements
Vitamin B6
Some children are helped by vitamin B6 supplements. In children who benefit from this treatment, the supplements help prevent intellectual disabilities and behavior problems. Vitamin B6 may also reduce the risk for blood clotting and eye and bone problems.

Ask your metabolic doctor whether your child would benefit from vitamin B6 supplements. Your doctor can do special tests to figure out whether your child will respond to vitamin B6.

BetaineThis is a vitamin-like substance found in grains and other foods. It can also be bought in pill form. It is sometimes used as a treatment for homocystinuria. It can help lower the amount of homocystine in the blood. It may also help lessen the risk of blood clots in people with this condition.
Betaine is a vitamin-like substance found in grains and other foods. It can also be bought in pill form as a supplement. Betaine can help lower the amount of homocystine in the blood, and may be especially helpful for children who do not respond to vitamin B6. It may also lessen the risk of blood clots.

Your metabolic doctor will decide whether your child needs betaine. Unless you are advised otherwise, use only betaine prescribed by your doctor.

Vitamin B12This is a type of B vitamin. It is also called cobalamin. It helps in the breakdown and use of food for energy. It also helps to make red blood cells and keep the nervous system healthy. It is found in meat, dairy products, and eggs. It can also be given by injection to people who have low levels or who have certain metabolic disorders.
Some people with homocystinuria have low levels of vitamin B12 in their blood. They may need to have vitamin B12 injections. Ask your doctor whether your child needs extra vitamin B12.

Folic AcidFolic acid is a form of vitamin B9. Folic acid is required to make healthy red blood cells and to prevent anemia. Folic acid can be found in certain foods and it can also be bought in pill form. It is recommended that people with Hemoglobin H take folic acid.
Some people have low levels of folic acid, a type of B vitamin, in their blood. They may need to take folic acid supplements by mouth. This vitamin can help lower the level of homocystine in the blood. Ask your doctor whether your child needs folic acid supplements.

L-cystineThis is one of 20 amino acids that make up protein. It is also called “cys.” It is made by the body and does not need to be eaten in the diet. It may be part of a special medical formula given to people with homocystinuria or certain other metabolic disorders. It can also be given as a supplement in pill form.
People with homocystinuria may have low levels of another amino acid called L-cystine. L-cystine may already be part of the special medical formula. If not, it can be taken by mouth as a supplement. Unless you are advised otherwise, use only L-cystine prescribed by your doctor.

Do not use any supplements or medications without checking with your metabolic doctor.

4. Blood and urine tests
Your child will have regular blood and urine tests to check his or her amino acid levels. Your child’s diet or formula may need to be adjusted based on blood test results.

5.  Pregnancy
Pregnancy increases the risk for blood clots, stroke, and heart disease in women with homocystinuria. Women are often given blood thinning medication during the last few months of pregnancy until about 6 weeks after delivery.

The usual treatments for homocystinuria should be continued during pregnancy. In addition to blood clots, untreated women are at higher risk for miscarriage and stillbirth.

WHAT HAPPENS WHEN HOMOCYSTINURIA IS TREATED?

With lifelong treatment, many children have normal growth and intelligence. Treatment may lower the chance for blood clots, heart disease, and stroke. Treatment also lessens the chance of eye problems. However, even when treated, some people still develop lens dislocation. This can often be corrected by surgery or other methods.

Children who begin treatment later in life may have intellectual disabilities and behavior problems.

WHAT CAUSES THE CBS ENZYME TO BE ABSENT OR NOT WORKING CORRECTLY?

Genes tell the body to make various enzymes. The CBS gene instructs the body to make the CBS enzyme. Everyone has two copies of the CBS gene. People with homocystinuria have changes, also called variants in both copies of their CBS genesA segment of DNA that contains the instructions to make a specific protein (or part of a protein). Genes are contained on chromosomes. Chromosomes, and the genes on those chromosomes, are passed on from parent to child. Errors in the DNA that make up a gene are called variants and can lead to diseases. that cause them to not work correctly. Because of the variantsA variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation. in the CBS genes, the CBS enzyme either does not work properly or is not made at all.

HOW IS HOMOCYSTINURIA INHERITED?

This condition is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Everyone has two copies of the CBS gene that make the CBS enzyme. In children with homocystinuria, neither copy of these genes works correctly. Children with homocystinuria inherit one non-working CBS gene from each parent.

Parents of children with homocystinuria rarely have the condition themselves. Instead, each parent has a single non-working gene for homocystinuria. They are called carriersA person who has one copy of a gene mutation for a particular autosomal recessive disorder (remember genes come in pairs). Carriers are not affected by the disorder. However, they can pass on the gene variant to their children. Children who inherit two such gene variants will be affected by the disorder. The term variants is now used in place of the term mutation.. Carriers do not have the condition because their other CBS gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have homocystinuria. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.

GeneticRelating to (or due to) genes and heredity or the field of studying genes and heredity. counseling is available to families who have children with this condition. Genetic counselors can answer your questions about how it is inherited, options during future pregnancies, and how to test other family members. Ask your doctor about a referral to a genetic counselorThese are health care providers who have special training in genetic conditions. They help families understand genetic disorders and how they are passed down. Genetic counselors offer information and support to people who have genetic conditions in their families or are concerned that they may have a child with an inherited disorder..

IS GENETIC TESTING AVAILABLE?

Genetic testing can be done on a blood sample. Genetic testing, also called DNA testing, looks for changes, also called variants, in the CBS genes that cause homocystinuria.

DNADeoxyribonucleic acid (DNA) is a molecule found in the chromosomes that carries genetic information. DNA is composed of four units (called bases) that are designated A, T, G, and C. The sequence of the bases spell out instructions for making all of the proteins needed by an organism. A gene is a section of DNA that holds the instructions for a specific protein. A change in one or more of the DNA bases making up a gene is called a mutation. Some mutations change the protein instructions and can lead to particular health problems or disorders. Each parent passes half of their chromosomes, and thus half of their DNA instructions, onto their children. It is these instructions that cause certain traits, such as eye or hair color, to be inherited. testing is not necessary to diagnose your child. It can be helpful for carrier testing or prenatal testing, discussed below.

WHAT OTHER TESTING IS AVAILABLE?

Homocystinuria is confirmed by special blood and urine tests. People with this condition usually have high levels of homocystine and methionine in their blood. Their urine usually has high levels of homocystine.

The condition can also be confirmed by testing the CBS enzyme in a skin sample.

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes (also called variants) have been found in your child, DNA testing can be done during future pregnancies. The sample needed for this test is obtained by either CVS or amniocentesisThis is a test done during pregnancy. A needle is used to remove a small sample of fluid from the sac around the fetus. The sample can be used to test for certain genetic disorders in the fetus. Amniocentesis to test for genetic conditions is usually done between 13 and 20 weeks of pregnancy..

If DNA testing would not be helpful, an enzyme test can be done using cells from the fetus. The sample needed for this test is obtained by amniocentesis.

Parents may either choose to have testing during pregnancy or wait until birth to have the baby tested. Parents may also choose to use assisted reproductive techniques to decrease the chance that their future children would have homocystinuria. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.

CAN OTHER MEMBERS OF THE FAMILY HAVE HOMOCYSTINURIA OR BE CARRIERS?

Having homocystinuria
If they are healthy and growing normally, older brothers and sisters of a baby with homocystinuria are unlikely to be affected. However, finding out whether other children in the family have the condition may be important. Early treatment could prevent serious health problems. Ask your metabolic doctor whether your other children should be tested.
           
Homocystinuria carriers
Brothers and sisters who do not have the condition still have a chance to be carriers like their parents. Except in special cases, carrier testing should only be done in people over 18 years of age.

If you are a parent of a child with homocystinuria, your brothers and sisters have a 50% chance to be a carrier. It is important for other family members to be told that they could be carriers. There is a chance they are also at risk to have children with homocystinuria.

Some states do not offer newborn screeningA screening test that looks for different disorders using a small sample of blood taken from a newborn’s heel. A positive or abnormal newborn screening result means that there are slight differences that were found in the baby’s blood, and further testing is needed to figure out if the baby has a metabolic disorder. for homocystinuria. However, expanded newborn screeningThe process of testing for disease in a person who does not show signs of having the disease (nonsymptomatic or asymptomatic person). The goal of screening is to catch the disease in its early stages. through private labs is available for babies born in states that do not screen for this condition. Your healthcare provider or genetic counselor can help you obtain expanded newborn screening.

CAN OTHER FAMILY MEMBERS BE TESTED?

Diagnostic testing
Brothers and sisters can be tested using blood, urine, or skin samples to determine if they also have this condition.

Carrier testing
If both gene changes (variants) have been found in your child, other family members can have DNA testing to see if they are carriers.

If DNA testing would not be helpful, other methods of carrier testing may be available. Your metabolic doctor or genetic counselor can answer your questions about carrier testing.

HOW MANY PEOPLE HAVE HOMOCYSTINURIA?

About one in every 200,000 to 300,000 babies in the United States is born with homocystinuria.

DOES HOMOCYSTINURIA HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

This condition occurs in all ethnic groups around the world. It is found more often in white people from the New England region of the United States. It is also more common in people with Irish ancestry. About one in every 50,000 babies in these groups has homocystinuria.

DOES HOMOCYSTINURIA GO BY ANY OTHER NAMES?

Homocystinuria is also called:

• Homocystinemia
• Cystathionine beta-synthase deficiency
• CBS deficiency

WHERE CAN I FIND MORE INFORMATION?

Metabolic Support UK
https://www.metabolicsupportuk.org

Baby’s First Test
http://www.babysfirsttest.org

MedlinePlus
https://medlineplus.gov/genetics/condition/homocystinuria/

HCU Network America
https://hcunetworkamerica.org/

DOCUMENT INFO:

Created by:	www.newbornscreening.info
Reviewed by:	HI, CA, OR, and WA metabolic specialists
Review date:	September 31, 2007 October 4, 2010 May 26, 2013 March 9, 2020 March 1, 2023
Update on:	March 1, 2023

 

DISCLAIMER:

THIS INFORMATION DOES NOT PROVIDE MEDICAL ADVICE. All content (“Content”), including text, graphics, images and information are for general informational purposes only. You are encouraged to confer with your doctor or other health care professional with regard to information contained on this information sheet. After reading this information sheet, you are encouraged to review the information carefully with your doctor or other healthcare provider. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. NEVER DISREGARD PROFESSIONAL MEDICAL ADVICE, OR DELAY IN SEEKING IT, BECAUSE OF SOMETHING YOU HAVE READ ON THIS INFORMATION SHEET. This project is supported by a grant from the MaternalHaving to do with the mother. and Child Health Bureau, Health Resources and Service Administration, Genetic Services Branch, MCH Project #:UH7MC30774-01-00 http://mchb.hrsa.gov