Argininosuccinic aciduria

Argininosuccinic aciduria is a genetic condition and there is no cure. A person will never outgrow the disorder. People with this disorder will have to be on a special diet and receive medications throughout their lives.

Some people with argininosuccinic aciduria may choose to stop following their diet as they get older. This is called poor compliance. A low protein diet is very restrictive and some people have trouble staying on the diet. Children, particularly older children, may stop following the diet because they are embarrassed or their classmates may make unkind comments. Children or teenagers who struggle with compliance should talk to their parents, physicians and a psychologist to work through these issues.

Sometimes people stop following the diet because it’s working well and they feel better. They may start to think that they do not need to follow the diet anymore or ‘cheat’ on the diet more and more often. However, the less they follow their diets, the more arginine and other compounds will keep building up in their bodies. The special diet to treat argininemia must be followed for life. Even if someone feels better and their symptoms improve, they need to continue to follow their treatment plan as developed by their physician and medical team in order to continue feeling better.

Parents and individuals should work closely with a metabolic dietitian in planning their diets. To find a metabolic dietitian specializing in diets for people with metabolic conditions, visit the GMDI Find a Metabolic Dietitian webpage.

In a family with argininosuccinic aciduria, tests can be done to see whether other family members are carriers for the disorder. (Carriers do not have symptoms and have one working and one non-working copy of the ASL gene.) However, the specific gene changes in that family needs to be known. If known, all siblings and other at-risk relatives can be tested. Molecular genetic testing, which are tests that look for changes to genes, can be performed. A newborn child in a family with a history of argininosuccinic aciduria should be tested through molecular genetic testing. A genetic counselor or a physician with experience in diagnosing and treating this disorder can provide advice about how a confirmed diagnosis can affect other family members. A listing of medical geneticists can be found at the American College of Medical Genetics and Genomics website and genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

Support groups are organizations that provide support, information, advice, referrals to physicians and medical centers, and up-to-date information on research and treatments. Support groups for argininosuccinic aciduria include the National Urea Cycle Disorders Foundation. This organization represents all urea cycle disorders.

There are also online communities for rare disorders such as RareConnect, RareShare, or Inspire, which allow individuals and parents to share experiences and advice about dealing with rare disorders.

Taking care of someone with a long-term or chronic condition can be tiring and challenging and this is no different for parents or other caregivers of people with argininosuccinic aciduria. If you are a caregiver in need of support, try to take time for yourself, set aside time for personal counseling, or look for other resources at the Caregiver Action Network. This organization works to improve the quality of life for people who care for loved ones with chronic conditions, disabilities, disease, or the frailties of old age.

Some organizations offer respite care. Respite care is when an elderly, handicapped, or ill person is temporarily put into a hospital or care center to provide relief so that the parents or other caretakers can take time to care for themselves. The Access to Respite Care and Help (ARCH) National Respite Network and Resource Center provides information about respite care and a locator service that can find respite care in your local area or state-run programs. The Children’s Respite Care Center provides comprehensive services and family support for children with special medical, developmental, cognitive and behavioral problems.

Support groups can also help provide support and advice for caregivers. Support groups for argininosuccinic aciduria include, The National Urea Cycle Disorders Foundation.

Argininosuccinic aciduria is a rare disorder. How severe the disorder is and how it affects a person can be very different. Some people do not develop symptoms; this is called being asymptomatic. Others develop severe and sometimes life-threatening complications during infancy or childhood. Because the severity of the disorder can be so different, it is difficult to make broad statements about prognosis or life expectancy because every person is unique. For the most part, doctors break down argininosuccinic aciduria into two forms: one in which symptoms begin in the newborn period and two in which symptoms begin at any point after the newborn period. There are times where this disorder can be fatal during infancy or early childhood. Doctors are studying argininosuccinic aciduria to better learn how and why symptoms develop and to determine the best ways to treat it. There are several drugs being studied and it is possible that new therapies will be offered in the coming years.

Argininosuccinic aciduria is a rare genetic disorder. People with this disorder are deficient in or missing an enzyme called argininosuccinate lyase or ASL. This enzyme has a job. It is part of the urea cycle. This cycle is series of biochemical reactions that occur in the body to help to break down (metabolize) and then remove excess nitrogen from the body. Nitrogen is obtained from the diet and is a normal waste product of the metabolism of protein. Through the urea cycle, nitrogen is broken down into a compound called urea that is passed from the body in the urine. Since people with argininosuccinic aciduria cannot properly break down nitrogen into urea, nitrogen (in the form of ammonia) build up in the body. When too much ammonia builds up, it is toxic to the body, particularly to the brain. The disorder is highly variable. This means how it affects one person can be very different from how it affects another person.

Argininosuccinic aciduria can be very severe right from birth, or there may be forms of the disorder that do not develop until after infancy; these are called late-onset forms. When the disorder occurs at birth, it can be severe and cause life-threatening problems. Infants may not eat well, may vomit, have irregular heartbeats, and be very tired (lethargic). If untreated, the disorder will worsen. Infants will become more lethargic, refuse to eat, can develop seizures, and may fall into coma. This called a metabolic crisis and occurs because of highly elevated ammonia levels. A metabolic crisis is a life-threatening complication that can be fatal.

The late-onset forms may have metabolic episodes similar to that seen in infants. Sometimes, symptoms may not occur unless something triggers an episode. This can include an infection, stress or when a child eats or drinks a lot of protein. Some children with late-onset forms develop intellectual disability, learning disabilities, seizures, and behavioral issues without any metabolic episodes. These problems can also develop in children who are treated from birth. Other problems may develop including liver damage, high blood pressure, and dry, brittle hair. The late-onset forms are quite variable. This means that can affect people very differently. For example, symptoms may not begin until childhood or the teen-age years. Sometimes, they don’t develop until people are adults.

Researchers have shown that infants and children with argininosuccinic aciduria have fewer episodes of metabolic crisis than infants and children with other urea cycle disorders. However, they have the second highest frequency of cognitive issues among these disorders. Researchers believe that some symptoms including neurological symptoms do not develop solely because of elevated ammonia levels. Researchers are not sure what other factors contribute to these symptoms.

Argininosuccinic aciduria is caused by gene changes in the ASL gene. People have about 20,000-25,000 genes in their bodies. Our genes contain our body’s genetic information, called DNA; genes are segments of DNA found on chromosomes. Genes are inherited from our parents and passed on to our children. Genes are like our body’s instruction manual – they control the growth, development and normal function of the body. Genes produce specific proteins that the body needs to grow and work properly. When there is an unexpected change in a gene, the protein that the gene produces may be absent or not work properly or be overproduced. A common type of gene change is a mutation, in which the DNA sequence that makes up a gene is altered. Mutations can be different sizes and can alter a gene in different ways. Sometimes, a mutation can affect multiple genes.

To find a medical professional nearby who can discuss information about gene changes in argininosuccinic aciduria, a listing of medical geneticists can be found at the American College of Medical Genetics and Genomics website and genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

Argininosuccinic aciduria is caused by a change (variant) in the ASL gene. Not all changes in a gene necessarily cause disease. If a change is known to cause galactosemia, it is known as a pathogenic or disease-causing variant. However, sometimes gene changes are found and scientists are unsure what it means, either because it has not been found before or has only been found in a few people. This is known as a variant of unknown significance. If you have a variant of unknown significance in the ASL gene, talk to your doctor about further testing that may help find out whether the gene change is pathogenic or not. A genetic counselor may also be able to help you review your test results. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

If your baby receives a positive result for argininosuccinic aciduria from newborn screening, it does not mean that your child definitely has the disorder. Newborn screening can cause "false positives." Further testing is needed to know for sure whether a child has the disorder. Doctors can also confirm a diagnosis through molecular genetic testing. These tests study the ASL gene for changes (mutations) that can cause the disorder.

Information about newborn screening can be found at Save Babies Through Screening Foundation or Baby’s First Test.

Rare diseases that affect multiple organ systems like argininosuccinic aciduria can benefit from a multidisciplinary approach. This approach involves healthcare professionals with specialized skills and expertise. They work together to make treatment recommendations and to provide quality care of individuals and families. Some people with argininosuccinic aciduria are asymptomatic, which means that they do not develop symptoms.

If symptoms do develop, then, depending upon the specific symptoms in an individual, a multidisciplinary team may include a specialist for neurological disorders in children (pediatric neurologist) who will monitor the function and health of the brain and central nervous system; a neurologist; a specialist who will monitor the health and function of the liver (hepatologist); a metabolic dietitian who will coordinate the nutritional management of people with metabolic diseases; a nutritionist who can help to develop a special diet; a genetic counselor who can help people understand the disease and the implications for the person and other family members; and a metabolic disease specialist.

Children who have argininosuccinic aciduria may benefit from psychological support. This means that they should receive help for any psychological or social problems they may have. Some children may feel different because they must be on a restrictive diet. Others may have learning disabilities or other problems that affect their performance in school. This can cause them to feel different from their friends and can lead to feelings of isolation, anxiousness, depression and frustration.

These are normal feelings for individuals and families dealing with a chronic illness. Talk to your doctor and medical team about how to deal with such issues. Parents and therapists can help children deal with these issues. It is also beneficial to talk to other people and families that are dealing with the same challenges. The National Urea Cycle Disorders Foundation puts people and families who have the same diagnosis in touch with one another. They offer a Mentor Program for newly-diagnosed families as well.

When infants and children have a chronic disorder like argininosuccinic aciduria, it can demand a lot of time and focus from parents. As with similar disorders, it is easy for healthy siblings to feel as if they have been pushed aside. Although studies have shown that siblings of children with chronic illness tend to develop strong levels of compassion and empathy, these studies have also shown that siblings can develop feelings of jealousy, anger, and high levels of anxiety. Parents can work with siblings by having clearly defined roles and responsibilities within the family structure. Siblings can help with the care of their sick sibling. Parents are encouraged to make time for activities, especially for healthy siblings, and to talk with and encourage healthy siblings to address their concerns and feelings. Some children may benefit from support outside of the immediate family including therapists or doctors. The Sibling Support Project is a nonprofit organization that serves the concerns and needs of siblings of people with special health, developmental, and mental health needs.

Argininosuccinic aciduria can be very severe right from birth, or there may be forms of the disorder that do not develop until after infancy. When the disorder occurs at birth or during infancy the disorder can be severe and may cause life-threatening problems. Infants may not eat well, may vomit, have irregular heartbeats, and be very tired (lethargic). The can also develop fluid around the brain or seizures. Their livers may be very large. They can have irregular heartbeats and low body temperature. Other problems may develop including liver damage and, although uncommon, kidney disease. They may have dry, brittle hair that falls out or breaks easily. If untreated, the disorder will worsen. This called a metabolic crisis and occurs because of highly elevated ammonia levels. Infants will become more lethargic, refuse to eat, can develop seizures, and may fall into coma. A metabolic crisis is a life-threatening complication that can be fatal. As infants and children age, they may also experience delays in reaching developmental milestones like sitting up or crawling and have intellectual disability.

When symptoms develop outside of the newborn period, this is called a late-onset form. The late-onset forms may have metabolic episodes similar to that seen in infants. These episodes usually happen after an infection, stress, when a child does eat a lot for a long time, or when a child eats or drinks a lot of protein. Some children with late-onset forms develop intellectual disability, learning disabilities, seizures, and behavioral issues without any metabolic episodes. High blood pressure is very common in people with argininosuccinic aciduria as well.

Argininosuccinic aciduria is highly variable. This means how the disorder affects one person can be very different from how it affects another. Some people do not develop any symptoms; they are known as asymptomatic. Others have very severe problems during infancy.

If an infant has a positive newborn screening test for argininosuccinic aciduria, then further testing will be done to confirm that the child has the disorder. If the diagnosis is confirmed, families should seek a medical consultation with a physician such as a metabolic genetic specialist with experience in treating the disorder. Treatment with special diet that is low in protein should be started immediately. Other initial steps will depend on how the disorder is affecting a person and when the disorder was diagnosed if it was not diagnosed through newborn screening.

Families should see a genetic counselor to help understand the genetic aspects of this disorder. Families may consider contacting a support group. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

The National Urea Cycle Disorders Foundation provides information, support, guidance, referrals and networking among other programs for individuals and families affected by urea cycle disorders like argininosuccinic aciduria.

Individuals with argininosuccinic aciduria should avoid a drug called valproic acid. This is an anti-seizure medication, also called an anti-convulsant. This drug may elevate ammonia levels in people with urea cycle disorders. They should also avoid intravenous steroids and, if they have liver disease, drugs that can damage the liver.

People with argininosuccinic aciduria must severely restrict the amount of protein in their diets. Although a low-protein diet is very restrictive, everyone needs some amount of protein. The body gets a lot of its amino acids through its diet. Amino acids a building blocks of protein. If the body cannot get enough amino acids through its diet, the body will begin to break down its own protein and this will lead to an increase in ammonia in the blood and tissues, and ammonia in high enough amounts is toxic to the brain.

So, when treating a urea cycle disorder like argininosuccinic aciduria, doctors and metabolic dietitians must balance the need for some protein against a person’s ability to break down protein. The amount of protein a person with argininosuccinic aciduria can tolerate can be different in one person when compared to another person. Many times, the amount of protein a person can tolerate will increase during infancy and childhood as they grow older.

In the United States, all 50 states include argininosuccinic aciduria on newborn screening. During routine newborn screening, a tiny sample of blood is taken from the heel of a newborn. This test, called a heel prick or Guthrie test, involves getting a few drops of blood from a pinprick in the newborn’s heel. The blood is run through a machine that can detect high levels of citrulline, an amino acid that abnormally builds up in people with argininosuccinic aciduria, and a few other disorders. Sometimes, newborn screening may miss an infant with the disorder, and sometimes there may be a false positive.

Additional tests will be performed to confirm the diagnosis. These tests involve looking at the blood and urine for substances that are abnormally elevated in argininosuccinic aciduria. In a blood sample, ammonia and citrulline may be elevated. High levels of ammonia are characteristic of all urea cycle disorders. Citrulline is an amino acid. Amino acids are building blocks of protein. Citrulline is elevated in the blood of children with argininosuccinic aciduria and argininosuccinate synthetase deficiency (another type of urea cycle disorder). Elevated levels of argininosuccinic acid may also be found in the blood or the urine.

Sometimes, doctors will take a sample of skin tissue. They will test certain cells called fibroblasts to determine the activity of the enzyme argininosuccinic lyase, which is reduced in people with this disorder. This is called an enzyme assay.

Information about newborn screening programs can be found at Save Babies Through Screening Foundation or Baby’s First Test.

As of July 2017, there were two clinical trials specific to argininosuccinic aciduria listed on clinicaltrials.gov, a government website that provides regularly updated information about federally and privately supported clinical trials. Both studies are looking into nitric oxide as a potential therapy. The enzyme argininosuccinate lyase is reduced in people with this disorder and this enzyme helps to create nitric oxide in the body. Nitric oxide is a compound that has many different functions in the body.

Although there were only 2 clinical trials, there were 12 trials investigating urea cycle disorders as a group. Argininosuccinic aciduria is classified as a urea cycle disorder. For the most up-to-date list, contact clinical trials.gov and search for argininosuccinic aciduria or urea cycle disorders.

Infants with argininosuccinic aciduria may be detected through newborn screening (NBS). NBS can detect elevated levels of citrulline in the dried blood spots. Additional tests will be performed to confirm the diagnosis. These tests involve looking at the blood and urine for substances that are abnormally elevated in argininosuccinic aciduria. In a blood sample, ammonia and citrulline may be elevated. High levels of ammonia are characteristic of all urea cycle disorders. Elevated levels of argininosuccinic acid may also be found in the blood or the urine. Sometimes, doctors will take a sample of skin tissue. They will test certain cells called fibroblasts to determine the activity of the enzyme argininosuccinic lyase, which is reduced in people with this disorder. This is called an enzyme assay.

Doctors may also conduct molecular genetic testing. Doctors recommend these tests to help create the most effective treatment plan or allow other family members to have genetic testing done. These tests involve studying the ASL gene for changes (mutations) that cause the disorder. This can include sequence analysis, where a part or sequence of DNA within a gene is examined, deletion/duplication analysis, where missing or extra regions of DNA are looked for within a specific gene, or targeted analysis, where know changes are looked for in the ASL gene. Molecular genetic testing must be done at specialized laboratories.

Treatment for argininosuccinic aciduria involves the long-term treatment of the disorder and managing a metabolic crisis or episode. People with this disorder cannot properly break down (metabolize) nitrogen, which the body gets from protein in the diet. This causes nitrogen, in the form of ammonia, to build up in the body. Doctors will place people on a low-protein diet. Individuals must remain on this diet for their lives and this can be challenging because the diet is very restrictive. Because protein intake is significantly reduced, people will need to receive a supplement that provides essential amino acids (building blocks of proteins) that they normally would get through eating protein. This includes the amino acid arginine. People with argininosuccinic aciduria cannot create arginine in sufficient levels. Doctors believe that supplementing the diet with arginine will help the body break down protein. Parents and individuals should work closely with a metabolic dietitian in planning their diets. To find a metabolic dietitian specializing in diets for people with metabolic conditions, visit the GMDI Find a Metabolic Dietitian webpage.

Doctors may also use medications that are called nitrogen scavengers. These drugs create a different way to break down and remove nitrogen from the body; this is called alternate pathway therapy. These drugs include Ammunol®, Buphenyl®, and Ravicti®.

Infants, children or adults can have episodes where their ammonia levels are very, very high. This is called a metabolic crisis or episode, metabolic decompensation or a hyperammonemic episode. This is a medical emergency that requires prompt treatment. Individuals must stop eating or drinking any protein. They may receive intravenous fluids that contain fats, a type of sugar called glucose, and insulin. They may also receive nitrogen scavenger drugs.

Sometimes these treatments will not lower ammonia levels fast enough. This may require hospitalization and doctors may use dialysis to remove the ammonia from the blood. This is the quickest way of removing excess ammonia from the body. Several different methods are available and hemodialysis is considered the fastest. Dialysis is a procedure where a machine filters your blood outside of your body. Your blood is drawn through a tube and passes through the machine where ammonia or other harmful substances are removed. The blood is then returned to the body.

If people have high blood pressure, doctors may recommend that they limit the salt in their diets and take drugs that lower blood pressure. Doctors do not know how effective these drugs are, but they can be tried. Recent research into nitric oxide therapy has shown that giving people nitric oxide has helped to lower blood pressure. This treatment is still being studied.

In certain people, a liver transplant may be recommended. This is considered a treatment of last resort and is reserved for people with significant liver damage, or in whom other treatments have not worked and they continue to have metabolic episodes and hospitalizations.

Sometimes, despite early and aggressive treatment, infants or children or adults still develop certain problems like seizures, behavioral issues, or cognitive impairment, which means they have problems with memory, thinking, problem solving, learning and similar skills.

Argininosuccinic aciduria is a complex genetic disorder and requires lifelong treatment. Individuals should be seen by specialists who have experience treating metabolic disorders, such as a medical geneticist and/or metabolic nutritionist. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. If you are looking for a metabolic clinic for treatment in the United States, you can search for the clinic or clinics in your state.

A patient registry is a database set up by researchers that contains information about patients with a particular disorder or group of disorders. This information helps researchers learn about a disorder, plan or study treatments, how a disorder progresses or affects people and other information. Patient registries require that patients either directly or through their doctor submit personal information. There is a patient registry for urea cycle disorders called The Urea Cycle Disorder International Patient Registry. The European Registry and Network for Intoxication type Metabolic Disorders has a European registry for urea cycle disorders.

Talk to a genetic counselor about the pros or cons of participating in a patient registry. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

People with argininosuccinic aciduria do not produce enough of the enzyme argininosuccinate lyase. This enzyme helps to create nitric oxide in the body. Nitric oxide is a compound that has many different functions in the body. Researchers are studying giving people nitric oxide as a treatment. In initial reports, nitric oxide therapy has shown some benefit. It has lowered blood pressure and resulting in mild neurological improvement. Researchers need to continue to study the disorder in clinical trials to determine if the therapy is safe and effective and how to best use it to treat people with argininosuccinic aciduria.

A person who is a carrier from argininosuccinic aciduria has a change in one of their two ASL genes. Argininosuccinic aciduria is an autosomal recessive disorder, which means that there must be a change in both ASL genes for the disorder to develop. Carriers of a mutation in one ASL gene do not develop symptoms of the disorder.

To find a medical professional nearby who can discuss information about gene changes in argininosuccinic aciduria, a listing of medical geneticists can be found at the American College of Medical Genetics and Genomics website and genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

The cost of special medical food for argininosuccinic aciduria can be different for one person or family when compared to another. There are many factors to consider. The supplier, the specific formula and medical foods, whether a person has insurance, whether the insurance plan will cover special medical foods, how much protein a person can handle in their diet, and other factors. For this reason, it is difficult to give an approximation about how much the use of medical food product would cost any given person. The cost is much more than it would be feed someone without argininosuccinic aciduria, and can be very expensive for an average family.

In the last few sessions (2017) of Congress, a bill has been introduced call the Medical Foods Equity Act. It has not been passed. This bill would require all federal programs to cover the cost of medical foods (formula and foods modified to be low in protein) for children and adults with argininosuccinic aciduria and similar disorders that require a special diet and supplemental medical foods.

Contact the National Urea Cycle Disorders Foundation (NUCDF) to learn about how much low-protein diet and supplemental medical foods may cost your family. The NUCDF may also have advice for dealing with insurance companies, information on state laws and policies on medical food and formula coverage, and links to the best places to find these products.

People with argininosuccinic aciduria remain on a special diet for life. The diet is a low-protein diet. It is a very restrictive diet overall and doctors know that some patients have trouble staying on the diet. Doctors advocate that people with argininosuccinic aciduria follow their special diet for life, and that people who have given up on the diet start following again as soon as possible. Sometimes, despite early diagnose and prompt treatment, including following a low protein diet, individuals will still develop symptoms. Parents and individuals should work closely with a metabolic dietitian in planning their diets. To find a metabolic dietitian specializing in diets for people with metabolic conditions, visit the GMDI Find a Metabolic Dietitian webpage.

We each get two copies of most of our genes from our parents. One copy comes from our mother and the other copy comes from our father. In argininosuccinic aciduria, both parents must pass along a nonworking copy of the ASL gene. Because of this, argininosuccinic aciduria is inherited in what is called an autosomal recessive pattern. People who have one working and one nonworking copy of the ASL gene are called carriers. When both parents are carriers, for each individual pregnancy, there is a 25% chance that both parents will pass along a nonworking copy of the gene and the child will have the disorder. There is a 50% chance that one parent will pass on the gene change and the other will not, meaning the child will be a carrier for the disorder. Finally, there is a 25% chance that both parents will pass along a working copy of the gene and the child will not have the disorder and will not be a carrier.

If you are interested in finding out if you are a carrier for argininosuccinic aciduria, talk to your doctor about testing or contact a genetic counselor in your area. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

Argininosuccinic aciduria is inherited in an autosomal recessive manner. This is one way a disorder or trait can be passed down through a family. Everyone has two copies of the ASL gene; one received from their father and one from their mother. Autosomal recessive inheritance means that a person receives a nonworking copy of the ASL gene from both parents. The parents have one working copy of the gene and one nonworking copy; they are carriers for argininosuccinic aciduria. Carriers do not develop symptoms of the disorder. If two people are carriers, there is a 25% chance with each pregnancy that their child will have the disorder and a 50% chance their child will also be a carrier for the disorder. There is also a 25% chance that the child will not have the disorder and will not be a carrier. If you have a family member with argininosuccinic aciduria and you would like to know if you are a carrier, talk to your doctor or meet with a genetic counselor to discuss testing options. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

Argininosuccinic aciduria can be classified as a urea cycle disorder or an amino acid disorder. People with this disorder have problems with an enzyme called argininosuccinate lyase. This enzyme is missing, deficient, or damaged. The argininosuccinate lyase enzyme has a job. It is part of the urea cycle. This cycle is series of biochemical reactions that occur in the body to help to break down (metabolize) and then remove excess nitrogen from the body. Nitrogen is obtained from the diet and is a normal waste product of the metabolism of protein. Nitrogen is broken down into a compound called urea that is excreted from the body in the urine. Because they cannot completely convert nitrogen into urea, nitrogen (in the form of ammonia) build up in the body.

Argininosuccinic aciduria is caused by a change in a gene called ASL. This gene produces an enzyme known as argininosuccinate lyase. An enzyme is a specialized protein that helps bring about chemical reactions in the body; they act as catalysts. Because of the gene change, people with argininosuccinic aciduria do not produce enough, or produce a damage form of this enzyme. Argininosuccinate lyase has a job. It is involved in the fourth step of the urea cycle. This cycle is series of biochemical reactions that occur in the body to help to break down (metabolize) and then remove excess nitrogen from the body. Nitrogen is obtained from the diet and is a normal waste product of the metabolism of protein. Nitrogen is broken down into a compound called urea that is passed from the body in the urine. People with argininosuccinic aciduria cannot properly break down nitrogen to urea. This causes nitrogen (in the form of ammonia) and other substances to build up in the body.

Ammonia is a neurotoxin, it damages cells of the central nervous system (which is made up of the brain and spinal). When ammonia levels get high enough, this can cause damage to the brain and central nervous system. However, some people with argininosuccinic aciduria develop neurological problems even when their ammonia levels are kept in balance since birth.

This has led researchers to believe that argininosuccinic aciduria is a more complex disorder than they originally thought. The symptoms occur for reasons other than the buildup of ammonia. Researchers are studying the disorder to try and determine these other factors.

Argininosuccinic aciduria can be diagnosed after a positive result from newborn screening. In the United States, all 50 states test for this disorder. During routine newborn screening, a tiny sample of blood is taken from the heel of a newborn. This test, called a heel prick or Guthrie test, involves getting a few drops of blood from a pinprick in the newborn’s heel. The blood is run through a machine that can detect high levels of citrulline, an amino acid that abnormally builds up in people with argininosuccinic aciduria, and a few other disorders. Sometimes, newborn screening may miss an infant with the disorder, and sometimes there may be a false positive.

Additional tests will be performed to confirm the diagnosis. These tests involve looking at the blood and urine for substances that are abnormally elevated in argininosuccinic aciduria. In a blood sample, ammonia and citrulline may be elevated. High levels of ammonia are characteristic of all urea cycle disorders. Citrulline is an amino acid. Amino acids are building blocks of protein. Citrulline is elevated in the blood of children with argininosuccinic aciduria and another urea cycle disorder called argininosuccinate synthetase deficiency. Elevated levels of argininosuccinic acid may also be found in the blood or the urine.

Sometimes, doctors will take a sample of skin tissue. They will test certain cells called fibroblasts to determine the activity of the enzyme argininosuccinic lyase, which is reduced in people with this disorder. This is called an enzyme assay.

Doctors may also conduct molecular genetic testing on infants with argininosuccinic aciduria. Doctors recommend these tests to help create the most effective treatment plan or allow other family members to have genetic testing done. These tests involve studying the ASL gene for changes (mutations) that cause the disorder. This can include sequence analysis, where a part or sequence of DNA within a gene is examined, deletion/duplication analysis, where missing or extra regions of DNA are looked for within a specific gene, or targeted analysis, where know changes are looked for in the ASL gene. Molecular genetic testing must be done at specialized laboratories.

If you believe your child may have argininosuccinic aciduria, talk to your pediatrician or a genetic counselor about your concerns. They can help decide if testing is right for you, and can order this testing if necessary. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

To learn about ongoing clinical research into argininosuccinic aciduria ask a physician who specializes in the disorder. Genetic counselors and medical geneticists are also excellence sources of information about ongoing clinical trials and can offer advice about the pros and cons about participating in such a trial. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website

Ongoing studies for argininosuccinic aciduria can also be found on clinicaltrials.gov, a service of the U.S. National Institutes of Health. In Europe, the EU Clinical Trial Register performs a similar service.

Support groups also have information about ongoing clinical trials as well as information and advice about participating in clinical trials. Support groups for argininosuccinic aciduria include the National Urea Cycle Disorders Foundation.

There are medical clinics and genetic clinics around the United States that can help people with metabolic disorders like argininosuccinic aciduria. The National Urea Cycle Disorders Foundation may be able to help you find a clinic or physician treating argininosuccinic aciduria near you. The Genetics and Rare Diseases Information Center has information on how to find a disease specialist. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. If you are looking for a metabolic clinic for treatment in the United States, you can search for the clinic or clinics in your state.
A metabolic dietician can be found through the Genetic Metabolic Dieticians International webpage.

Some people with argininosuccinic aciduria find it challenging when it’s time to move (transition) from pediatric to adult health care services. One big change is leaving a doctor with whom you have a long-standing relationship, a doctor who is familiar with both your condition and you. It can feel like ‘starting over’ as you’ll begin to work with new doctors and a new medical team. Another challenge in moving to adult care is that young adults must take greater responsibility for their health. They must manage their disorder and manage their medications. They must bear greater responsibility for decisions concerning their health. Adolescents should be encouraged to make decisions about their care as early as possible to make this transition easier. Some hospitals have programs to help children with chronic disease transition to adult care services.

Support groups may also provide information or support on how to move from pediatric care to adult care services and what to expect. The National Urea Cycle Disorders Foundation provides information and support for families dealing with argininosuccinic aciduria.

Some children with argininosuccinic aciduria may have intellectual disability or experience delays in reaching developmental milestones. This can make school more challenging. These children may need special accommodations in school. They are eligible for an individual education plan (IEP) or a 504 plan.

An IEP is a document that helps to guide the education of a child with a disability or special needs and ensures that they have access to the same educational opportunities as all children. The plan is individualized for each student.

A 504 plan ensures that students with disabilities can fully participate in school and have access to the same educational opportunities as all children. This plan is important for making sure a student with argininosuccinic aciduria can maintain their diet while fully participating in school with the same access to educational opportunities as all children.

Even children who received an early diagnosis and prompt treatment and do not have symptoms are eligible for a 504 plan. A 504 plan organizes any unique requests needed by a child to fully participate in school. This plan is important for making sure a student with argininemia can maintain their diet in school while fully participating in school with the same access to educational opportunities as all children.

Parents should talk to their child’s school system and learn what they need to do for their children. Parents are encouraged to provide a school with a packet of information on argininosuccinic aciduria to school officials including teachers, nurses, psychologists, the principal, and other professionals. The National Urea Cycle Disorders Foundation has a guide for educating school officials called, An Educator’s Guide to UCD.

The U.S. Department of Education has information on individual education plans and on 504 plans. Global Genes, a rare disease advocacy organization, has a RARE Toolkit that advises parents on advocating for their children at their school.

Argininosuccinic aciduria is a rare disorder. Rare disorders often go unrecognized or misdiagnosed and how common they are in the world is often unclear or unknown. In the United States and Europe, estimates for the frequency of argininosuccinic aciduria range from 1 in 70,000 to 1 in 218,000 births. Argininosuccinic aciduria is classified as a urea cycle disorder. The frequency of these disorders collectively, is about 1 in 30,000 people.

There are several things that can make a urea cycle disorder worse. This is includes eating a lot protein, surgery, having another illness like a viral infection, or certain drugs like valproic acid, which is used to treat seizures. These things create stress on the urea cycle, the series of biochemical steps through which the body breaks down (metabolizes) and removes nitrogen from the body. Nitrogen is obtained from protein in the diet. These things can lead to a buildup of ammonia and other substances in the blood and the body. However, significantly increased ammonia levels can occur and is a life-threatening complication the requires hospitalization.

People with argininosuccinic aciduria should be able to travel safely and enjoyably. People or families need to be prepared when traveling, particularly when traveling by air or internationally. If you are traveling and you or your child has argininosuccinic aciduria, you may want to bring a letter from your physician explaining the medical necessity of any food or formula you are bringing with you. You may also carry information about their condition when they travel in case there is a medical emergency. People with argininosuccinic aciduria should have an emergency card that explains their disorder. If you are traveling abroad, you may want to contact your medical team to see where appropriate food and formula can be obtained and whether your destination has adequate medical facilities.

How families travel with a child with argininosuccinic aciduria can also depend on the types of neurological problems a child has. Support groups and other parents or families with argininemia can offer advice and information and how to make traveling easier and safer. Support groups for argininosuccinic aciduria include, The National Urea Cycles Disorders Foundation.

Some parents may choose to have their child tested for argininosuccinic aciduria before they are born. This is known as prenatal diagnosis. If the gene change(s) that causes argininosuccinic aciduria are known in a family, then molecular genetic testing (which can detect these changes) can be used for prenatal diagnosis. A sample of tissue can be taken from the placenta to test for changes in the ASL gene. This test is called chorionic villus sampling. Another test is called amniocentesis, which involves taking a sample of the amniotic fluid that surrounds and protects a developing fetus. Cells known as amniocytes are taken from the fluid and studied for changes in the ASL gene. There are risks to the unborn baby of doing these tests before birth.

If molecular genetic testing is not possible, doctors can make a prenatal diagnosis through biochemical testing. This testing can detect elevated levels of argininosuccinic acid in amniotic fluid. Doctors can also use chorionic villus sampling or amniocentesis to test for the activity of the argininosuccinate lyase enzyme, which is reduced in infants with argininosuccinic aciduria.

Talk to your doctor or a genetic counselor in your area to discuss the risks and benefits of prenatal diagnosis. Genetic counselors can be found on the National Society of Genetic Counselors website in the United States, and in Canada at the Canadian Association of Genetic Counsellors website.

Argininosuccinic aciduria is one name that doctors and medical professionals may use to describe this disorder. Other names include:

Support groups are organizations that provide support, information, advice, referrals to physicians and medical centers, and up-to-date information on research and treatments. The National Urea Cycle Disorders Foundation is a nonprofit organization dedicated to the identification, treatment and cure of urea cycle disorders like argininosuccinic aciduria.

There are also organizations that provide support and information for metabolic disorders like argininemia as a group. These organizations are called umbrella organizations. They represent many different metabolic disorders including the urea cycle disorders and include Children Living with Inherited Metabolic Diseases and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD).

Some infants and children with argininosuccinic aciduria may have intellectual disability or experience delays in reaching developmental milestones. The first few years of a child’s life are critically important to a child’s development. States have federally-funded early intervention programs that support families that have concerns or issues with their children’s development up to the age of three. Some states will continue to offer early intervention programs beyond the age of three. Other states will transition a child into school-based programs that can be provided at home. In some states, a child may be eligible for early intervention services at no charge. Other states may charge a fee, depending on the agencies involved.

Other countries and areas may have other funded programs or resources.

Talk to your doctor and medical team about early intervention programs in your state and whether these resources will appropriate and beneficial for your child. The Centers for Disease Control and Prevention (CDC) provide information about early intervention programs and assistance.