AMINO ACID DISORDER

Disorder name: Citrullinemia
Acronym: CTLN1
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• What is citrullinemia?
• What causes citrullinemia?
• If citrullinemia is not treated, what problems occur?
• What is the treatment for citrullinemia?
• What happens when citrullinemia is treated?
• What causes the ASS enzyme to be absent or not working correctly?
• How is citrullinemia inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have citrullinemia or be carriers?
• Can other family members be tested?
• How many people have citrullinemia?
• Does citrullinemia happen more often in a certain ethnic group?
• Does citrullinemia go by any other names?
• Where can I find more information?

This fact sheet contains general information about citrullinemia. 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. All children with this condition should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS CITRULLINEMIA?

Citrullinemia is one type of amino acid disorder. People with this condition cannot remove ammonia from the body. AmmoniaThis is a waste product made when protein is broken down for the body to use. Ammonia is harmful to the body. It is usually changed to a harmless substance called “urea.” Urea is then removed from the body in the urine. People with urea cycle disorders cannot get rid of ammonia. If these conditions are not treated, ammonia can build up and cause serious health problems. is a harmful substance. It is made when 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. and its building blocks, 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., are broken down for use by the body.

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. Protein is made up of smaller building blocks called amino acids. 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 CITRULLINEMIA?

This is one of a small number of conditions called “urea cycle disordersThese are inherited conditions that cause ammonia to build up in the body. Ammonia is a harmful waste product made during the breakdown of protein and its amino acid building blocks.” (UCD).

Citrullinemia is caused by problems with the enzyme “argininosuccinate synthetase” (ASS). In people with citrullinemia, the ASS enzyme is either missing or not working properly. This enzyme’s job is to help break down certain amino acids and to remove ammonia from the body.

When ASS is not working, an amino acid called citrulline builds up in the blood. Ammonia and other harmful substances also build up. This causes brain damage. If not treated, excess ammonia in the blood can cause death.

IF CITRULLINEMIA IS NOT TREATED, WHAT PROBLEMS OCCUR?

Normally, the body changes ammonia into a substance called “ureaThis is a harmless waste product made by the body. Its job is to get rid of ammonia, a harmful substance made when protein is broken down for use by the body. The kidneys flush urea from the body in the urine..” Urea is then safely removed in the urine. However, if ammonia is not changed to urea, high levels of ammonia build up in the blood. This can be very harmful. If ammonia levels stay high for too long, severe brain damage can occur.

The symptoms of citrullinemia and the age they start, vary from person to person. The most common type is called “classic” citrullinemia. It usually starts in infancy. There are milder types that start later in infancy, childhood, or later. Some women with citrullinemia only have symptoms during or after pregnancy.

Classic citrullinemia
Infants seem healthy at birth but quickly develop symptoms. Within a few days of life, babies will have high levels of ammonia in their blood. Some of the first symptoms of high blood ammonia are:

• poor appetite
• extreme sleepiness or lack of energy
• irritability
• vomiting

If not treated, high ammonia levels cause:

• muscle weakness
• decreased or increased muscle toneIn order to hold our posture and control our movements, a certain amount of tension is needed in our muscles. This tension is called “muscle tone.” People with hypotonia have too little tension in their muscles and appear “floppy.” People with hypertonia have too much tension in their muscles and have problems with tight, rigid muscles and joints.
• breathing problems
• problems staying warm
• 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.
• swelling of the brain
• comaThis is a sleep-like condition from which a person cannot be awakened. People in a coma are unconscious. A coma can be caused by many things. Two causes are untreated low blood sugar (hypoglycemia) and a metabolic crisis., and sometimes death

Other effects of citrullinemia can include:

• poor growth
• enlarged liver
• learning delays or intellectual disabilities

Without treatment, most babies die within the first few weeks of life.

Milder types
In the milder types, symptoms start later in infancy or childhood. Symptoms in untreated children can include:

• poor growth
• dry, brittle hair
• hyperactivityThis refers to children who are unusually overactive. These children have serious problems sitting still. They tend to fidget and run around much more than usual. Some children with hyperactivity need treatment. They may be helped by behavior treatment, medication or both of these therapies.
• behavior problems
• learning problems or intellectual disabilities
• avoidance of meat and other high-protein foods
• spasticityThis is rigidity of the muscles and increased reflexes. It is caused by increased muscle tone. It results in abnormal tightness or stiffness of the muscles and joints.
• Cerebral infarction (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.)
• episodes of high levels of ammonia in the blood
• liver failure

Episodes of high blood ammonia often happen:

• after going without food for long periods of time
• during illness or infection
• after high-protein meals

Some of the first symptoms of high blood ammonia in children are:

• poor appetite
• severe headache
• vomiting
• extreme sleepiness or lack of energy
• slurred speech
• poor coordination or balance problems

If not treated, children with high blood ammonia levels may develop:

• breathing problems
• swelling of the brain
• seizures
• coma, sometimes leading to death

A rare type of citrullinemia occurs during and after pregnancy. Women may experience:

• episodes of vomiting
• lethargyAbnormal drowsiness.
• seizures
• confusion and hallucinations
• behavioral changes including manic episodes and psychosisThis is a mental disorder in which the person is not in contact with reality. It can include sensing things that aren’t really there (hallucinations) or having beliefs that aren’t based on reality (delusions).
• swelling of the brain

Some people have very mild or no symptoms and are only diagnosed with citrullinemia after their brother or sister is diagnosed.

WHAT IS THE TREATMENT FOR CITRULLINEMIA?

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 the build-up of ammonia. You should start treatment as soon as you know your child has the condition.

The following are treatments often recommended for babies and children with citrullinemia:

1.  Low-protein diet and/or special medical foods and formula
Most children need to eat a diet made up of very low-protein foods, special medical foods, and sometimes, a special formula. Your 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 create a food plan that contains the right amount of protein, nutrients, and energy to keep your child healthy. A special food plan should be continued throughout your child’s life.

Low-protein diet
The most effective treatment for citrullinemia is a diet with low amounts of protein. Foods that are high in protein need to be avoided or strictly limited include:

• milk, cheese, and other dairy products
• meat and poultry
• fish
• eggs
• dried beans and legumes
• nuts and peanut butter

Eating foods high in protein can cause ammonia to build up, causing severe illnesses.  Many vegetables and fruits have only small amounts of protein and can be eaten in carefully measured amounts.

It is important not to remove all protein from your child’s diet. Your child still needs a certain amount of protein for normal growth and development. Any changes in the diet should be made under the guidance of a dietvician.

Medical foods and formula
There are medical foods such as special low-protein flours, pastas, and rice that are made especially for people with amino acid disorders.

Your baby may need to drink a special medical formula that contains the correct amount of amino acids and nutrients. Your metabolic doctor and dietician will decide whether your child needs this treatment. Some states offer help with payment for this special formula and others require private insurance to pay for the formula and other special medical foods.

Your child’s exact food plan will depend on many things such as his or her age, weight, and general health. Your dietician will fine-tune your child’s diet over time.  Any diet changes should be made under the guidance of a dietician.

2.  Medication
There are certain medications that can help the body get rid of ammonia. These medications are taken by mouth or by tube feeding to prevent high ammonia levels. Your doctor will decide whether your child needs these medications, which ones, and how much to use.

During episodes of high ammonia, children need to be treated in the hospital.  Medications to remove ammonia are often given by IVThis is a small tube placed into a vein, usually in the hand or arm. Medications and nutrients can be given through this tube directly into the blood. IV’s are often used in the hospital to give fluids, glucose and medication over a long period of time.. Dialysis is sometimes needed to remove ammonia from the blood.

An amino acid called arginine is often given by mouth to help prevent ammonia build-up. Your doctor will tell you whether your child needs arginineThis is one of 20 amino acids that make up protein. It is also known as “Arg.” Most of the arginine needed is made by the body. In most cases, it does not need to be eaten in the diet. Arginine can also be bought in pill form. Children with certain urea cycle disorders are often given arginine supplements. These supplements can help clear the body of ammonia. and how much to use. Do not use any supplements or medications without checking with your doctor.

3.  Blood tests 
Your child will have regular blood tests to measure ammonia and amino acid levels. Your child’s diet and medication may need to be adjusted based on blood test results.

4.  Call your doctor at the start of any illness
For some babies and children with citrullinemia, even minor illnesses can cause high ammonia levels. In order to prevent problems, call your doctor right away when your child has any of the following:

• loss of appetite
• low energy or extreme sleepiness
• vomiting
• fever
• infection or illness
• behavior or personality changes
• difficulty walking or balance problems

Symptoms of high ammonia often need to be treated in the hospital.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

5.  Liver transplantation

Liver transplant surgery is an optional treatment for people with citrullinemia. The ASS enzyme that causes citrullinemia is located in the liver. Because of this, some children with citrullinemia have had liver transplantation surgery (removal of their liver and replacement with a donor liver) to treat their citrullinemia symptoms.

Liver transplant is a major surgical procedure and has some risks. Individuals who have had a liver transplant must take medication for the rest of their lives to prevent their body from rejecting the donor liver. However, successful liver transplantation has been reported to improve quality of life and prolong survival in some cases. Liver transplantation does not reverse neurologic problems if they have already occurred.

Many factors must be considered before surgery and this option should be discussed very thoroughly with your child’s physicians.

WHAT HAPPENS WHEN CITRULLINEMIA IS TREATED?

With prompt and lifelong treatment, children with citrullinemia can often live healthy lives with typical growth and learning. Early treatment can help prevent high ammonia levels which decreases the risk for brain damage.

Even with treatment, some children still have episodes of high ammonia. This can result in brain damage. This can cause lifelong learning problems, intellectual disabilities, or spasticity.

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

Genes tell the body to make various enzymes. The ASS1 gene instructs the body to make the ASS enzyme. Everyone has two copies of the ASS1 gene. People with citrullinemia have changes, also called variantsA variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation., in both copies of their ASS1 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 variants in the ASS1 genes, the ASS enzyme either does not work properly or is not made at all.

HOW IS CITRULLINEMIA INHERITED?

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

Everyone has two copies of the ASS1 genes that make the ASS enzyme. In children with citrullinemia, neither of these genes works correctly. Children with citrullinemia inherit one non-working gene for the condition from each parent.

Parents of a child with citrullinemia rarely have the condition themselves. Instead, each parent has a single non-working ASS1 gene for citrullinemia. 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 ASS1 gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have citrullinemia. 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, choices 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 (variants) in the ASS1 genes that cause the condition.

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 or prenatal testing, discussed below.

WHAT OTHER TESTING IS AVAILABLE?

Special tests on blood, urine, or skin samples can be done to confirm citrullinemia. Talk to your metabolic doctor or genetic counselor if you have questions about this type of testing.

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes (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 on cellsThe smallest living unit. Cells make up all organs and tissues in multi-cellular organisms, like humans. They can also live independently, as in bacteria and other microorganisms. At a minimum, a cell is surrounded by a membrane, contains DNA at some stage in its life, and is able to replicate itself into two equal parts. from the fetus. Again, the sample needed for this test is obtained by either CVSThis is a special test done early in pregnancy. During CVS, a small sample of the placenta is removed for testing. This sample can be used to test for certain genetic disorders in the fetus. CVS is usually done between 10 and 12 weeks of pregnancy. or amniocentesis.

Although prenatal testing is possible, many parents choose to 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 citrullinemia. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing after birth.

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

Having citrullinemia

The brothers and sisters of a baby with citrullinemia have a chance of being affected, even if they haven’t had symptoms. Finding out whether other children in your family have the condition is important because early treatment can prevent serious health problems. Talk to your metabolic doctor or genetic counselor about testing your other children.

Citrullinemia carriers
Brothers and sisters who do not have citrullinemia 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 citrullinemia, 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 citrullinemia.

All states 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 citrullinemia. However, when both parents are carriers, 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. results are not sufficient to rule out the condition in a newborn baby. In this case, special diagnostic testing should be done in addition to newborn screening.

CAN OTHER FAMILY MEMBERS BE TESTED?

Diagnostic testing
Brothers and sisters of a child with citrullinemia can be tested using blood, urine, or skin samples to see if they also have this disorder.

Carrier testing
If both gene changes in the ASS1 genes have been found in your child, other family members can have genetic 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 CITRULLINEMIA?

This is a rare condition. About one in every 57,000 babies in the United States is born with citrullinemia.

DOES CITRULLINEMIA HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

The classic form of citrullinemia occurs in all ethnic groups around the world.

DOES CITRULLINEMIA GO BY ANY OTHER NAMES?

Citrullinemia is sometimes also called:

• Citrullinemia, type 1 (classic form)
• Argininiosuccinate synthetase deficiency
• Arginininosuccinic acid synthetase deficiency
• ASS deficiency
• Citrullinuria
• CTLN1

The adult-onset form of citrullinemia is also called:

• Late-onset citrullinemia

A disorder which was originally thought to be related to Citrullinemia but is now known to be a separate disorder is called:

• Citrullinemia, Type II
• Citrin Deficiency

WHERE CAN I FIND MORE INFORMATION?

National Urea Cycle Disorders Foundation
http://www.nucdf.org/

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

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

Urea Cycle Disorders Consortium
https://www1.rarediseasesnetwork.org/cms/ucdc

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

 

DOCUMENT INFO:

Created by:	www.newbornscreening.info
Reviewed by:	HI, CA, OR, and WA metabolic specialists
Review date:	September 31, 2007 September 21, 2010 May 20, 2013 March 9, 2020 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