Citrullinemia type I is a rare inherited disease of the urea cycle, which is the process in the liver that removes extra nitrogen from the body. In this disease, the body cannot remove nitrogen properly, so a toxin called ammonia builds up in the blood. This high ammonia can quickly hurt the brain and other organs if it is not treated.
Citrullinemia type I is a rare inherited urea-cycle disorder caused by a problem in the ASS1 gene, which makes the enzyme argininosuccinate synthetase. When this enzyme does not work properly, the body cannot remove nitrogen waste, so toxic ammonia builds up in the blood. High ammonia can damage the brain and other organs, especially in newborns and children. Treatment focuses on keeping ammonia low using diet, medicines, and sometimes liver transplant. Early diagnosis through newborn screening and fast emergency care are very important to prevent brain injury and disability.
In citrullinemia type I, there is a problem with an enzyme called argininosuccinate synthetase 1 (ASS1). This enzyme works in the urea cycle to turn a substance called citrulline into another substance called argininosuccinate. When the enzyme does not work well, citrulline and ammonia rise to very high levels.
Citrullinemia type I usually starts in the newborn period, often in the first few days of life, with feeding problems, vomiting, sleepiness, and breathing troubles. Some people, however, may show milder or later signs in childhood or adulthood. Without quick treatment, high ammonia can cause seizures, coma, and even death, so this condition is a medical emergency when acute symptoms appear.
Other names
Citrullinemia type I is known by several other medical names. These names all point to the same basic problem: lack of the ASS1 enzyme in the urea cycle.
Classic citrullinemia – This name is used because this is the “classic” urea cycle disorder with very high citrulline and ammonia levels.
Citrullinemia, classic (CTLN1) – “CTLN1” is the short code used in genetic and medical books for citrullinemia type I.
Argininosuccinate synthetase deficiency – This name focuses on the missing or weak enzyme argininosuccinate synthetase (ASS1).
ASS1 deficiency (ASS deficiency) – “ASS1” is the gene that gives the body instructions to make the ASS1 enzyme; when it is faulty, the enzyme is low.
Argininosuccinic acid synthase deficiency – Another way to write the same enzyme name, often seen in older articles.
Citrullinuria / CIT – These shorter names were used in the past to describe high citrulline in the urine and blood.
Types of citrullinemia type I
Doctors describe several forms or “types” of citrullinemia type I based on how severe it is and when symptoms begin. The basic gene problem is similar, but the age at onset and seriousness can be different.
Classic neonatal citrullinemia type I – This is the most common and most severe form. A baby who seemed normal at birth quickly becomes very sick in the first few days of life due to very high ammonia levels.
Late-onset citrullinemia type I – In this form, symptoms start later in childhood, the teen years, or adult life. People may have repeated episodes of confusion or behavior change caused by high ammonia, but sometimes they are well between attacks.
Mild or partial citrullinemia type I – Some people have gene changes that leave a small amount of enzyme working. They may have mild symptoms, mild high ammonia, or be found only by screening tests.
Asymptomatic biochemical form – A few people are found to have high citrulline levels on blood tests but have no clear symptoms. They may be carriers or have a very mild form that still needs monitoring.
Carrier state – Carriers have one changed copy of the ASS1 gene and one normal copy. They usually have no symptoms, but two carriers can have a child with full citrullinemia type I.
Causes and risk factors
Citrullinemia type I is mainly caused by changes (mutations) in the ASS1 gene. It is an autosomal recessive condition, which means a child must get a faulty gene copy from both parents. Below are 20 simple “causes and risk factors” that include the main genetic cause and the things that increase the chance or severity of disease episodes.
ASS1 gene mutations – The direct cause is a harmful change in both copies of the ASS1 gene, which stops the enzyme from working well and leads to citrullinemia type I.
Autosomal recessive inheritance – Because this is autosomal recessive, parents who each carry one faulty ASS1 gene have a 25% chance in every pregnancy to have a baby with citrullinemia type I.
Homozygous mutations – Some patients inherit the same ASS1 mutation from both parents (homozygous), which usually causes a classic, severe form of the disease.
Compound heterozygous mutations – Others inherit two different harmful ASS1 mutations (compound heterozygous); together they still make the enzyme weak and cause disease.
Novel or rare mutations – Many families have very rare or new ASS1 mutations, so genetic testing is needed to confirm the exact change in each family.
Family history of citrullinemia – Having a brother, sister, or close relative with citrullinemia type I increases the chance that other children in the family could be affected or be carriers.
Parental carrier status – Parents from families or regions with known ASS1 mutations are more likely to be carriers and to have an affected child if both are carriers.
Consanguinity (related parents) – When parents are blood relatives (such as cousins), the chance that both carry the same rare ASS1 mutation is higher, which raises the risk of having a child with citrullinemia type I.
Certain population clusters – Some studies show higher rates of ASS1 mutations in certain ethnic groups or regions, so babies from these groups may have a higher risk.
High protein load in a newborn with ASS1 deficiency – In an affected baby, normal feeding with protein can quickly raise ammonia because the urea cycle is not working, so feeding acts as a trigger for the first crisis.
Infection and fever – In older children or adults with citrullinemia type I, infections can break down body proteins and suddenly push ammonia levels higher, leading to an attack.
Fasting or poor intake – Skipping meals or fasting increases protein breakdown in the body, which raises ammonia production and can trigger symptoms in people with limited ASS1 activity.
High-protein diet in older patients – Eating too much protein at once can overload the weak urea cycle, causing ammonia to rise and leading to confusion or behavior changes.
Certain medicines that increase catabolism – Some drugs (for example, high-dose steroids or some chemotherapy) can make the body break down its own proteins faster, which increases ammonia load in patients with citrullinemia type I.
Surgery or major stress – Operations and severe stress states can increase protein breakdown and ammonia production, which is dangerous in people with urea cycle disorders.
Liver failure or added liver stress – Because the urea cycle runs mainly in the liver, any extra liver injury (such as viral hepatitis or fatty liver) can worsen the enzyme problem and raise ammonia more.
Delay in diagnosis after newborn screening – If newborn screening is not done or follow-up is delayed, the baby may have several feeding days before anyone knows, which allows ammonia to reach dangerous levels.
Poor adherence to low-protein diet – In known patients, not following a special low-protein diet and not taking prescribed medicines can cause repeated hyperammonemia episodes.
Pregnancy in women with mild citrullinemia type I – Pregnancy is a high-metabolism state; women with urea cycle disorders may have increased risk of hyperammonemia if treatment is not carefully adjusted.
Lack of emergency treatment plan – When families and doctors do not have a clear emergency plan for illness or poor intake, treatment for rising ammonia can be delayed, which makes the underlying enzyme defect more dangerous.
Symptoms and signs
The symptoms of citrullinemia type I mostly come from high ammonia levels affecting the brain and body. Symptoms can appear suddenly and get worse very fast, especially in newborns.
Poor feeding in newborns – Babies may not want to suck, may stop feeding early, or refuse the bottle or breast because they feel sick when ammonia rises.
Frequent vomiting – Repeated vomiting is common and is often one of the first clear signs that there is a serious metabolic problem in the baby.
Lethargy (very sleepy, hard to wake) – Babies and older patients may become unusually sleepy or difficult to wake as ammonia affects the brain, which is a warning sign of possible encephalopathy.
Irritability and fussiness – Before they become very sleepy, babies may cry a lot and seem uncomfortable because their brain is starting to be affected.
Loss of appetite in older children and adults – Children or adults may lose interest in food and not want to eat when ammonia levels rise, sometimes during illness or after a high-protein meal.
Headache and feeling “foggy” – Older children and adults can complain of headache, feeling confused, or having trouble thinking clearly when ammonia is elevated.
Behavior changes – Sudden changes such as agitation, strange behavior, or personality change can be signs of hyperammonemia in late-onset citrullinemia type I.
Seizures – Fits or convulsions may occur when ammonia is very high and the brain is severely affected, both in infants and in older patients.
Low muscle tone (hypotonia) – Babies may feel “floppy” because high ammonia disrupts signals between the brain and muscles, causing weak tone.
Breathing problems – Rapid breathing or periods of breathing difficulty can appear as the body tries to fix acid-base changes caused by the metabolic problem.
Liver enlargement (hepatomegaly) – Some patients develop a larger liver, which can be felt on exam or seen on imaging, because the liver is under stress from the urea cycle defect.
Cerebral edema (brain swelling) – In severe hyperammonemia, fluid can build up in the brain, leading to increased pressure inside the skull, which is life-threatening.
Coma – If ammonia remains very high and is not treated in time, the patient may become unresponsive and slip into coma, a medical emergency.
Long-term developmental delay – Children who survive severe episodes may later show learning problems, speech delay, or reduced school performance because of past brain injury.
Attention and behavior disorders – Some studies suggest a link between citrullinemia type I and attention or behavior problems such as ADHD, especially when ammonia episodes have occurred.
Diagnostic tests for citrullinemia type I
Doctors use a mix of clinical examination and tests to diagnose citrullinemia type I and to check how severe it is. Often, newborn screening gives the first clue, and then more detailed tests confirm the diagnosis.
Physical examination tests
General newborn physical exam – The doctor checks how the baby looks, how they move, and how they feed, and looks for signs like poor sucking, low muscle tone, or unusual sleepiness, which can suggest a metabolic problem such as citrullinemia type I.
Neurological exam – The doctor checks how well the baby or child responds, moves, and reacts to touch and light, to see if the brain is affected by high ammonia. Things like floppy muscles, weak reflexes, or seizures can point towards a urea cycle disorder.
Vital signs assessment – Heart rate, breathing rate, temperature, and blood pressure are checked. Abnormal breathing or low blood pressure can mean serious illness from hyperammonemia and brain swelling.
Abdominal examination – The doctor gently feels the belly to look for an enlarged liver, which can be a clue to liver stress from a urea cycle disorder.
Growth and head size measurements – Weight, length, and head circumference are checked and compared to age charts, because repeated high ammonia and illness can affect growth and brain development over time.
Manual tests (bedside and functional assessments)
Glasgow Coma Scale (GCS) scoring – In older infants, children, and adults, doctors may use a simple scoring system to rate eye opening, speech, and movement to judge how awake the person is and how badly the brain is affected.
Assessment of muscle tone and reflexes – The examiner moves the patient’s arms and legs and taps reflex points to look for floppy muscles or abnormal reflexes, which can happen in severe hyperammonemia.
Manual coordination and balance checks – In older children and adults, simple tasks like touching a finger to the nose or walking in a straight line can show subtle brain problems from repeated ammonia episodes.
Manual assessment of hydration status – The doctor checks skin turgor, mouth moisture, and capillary refill to see if vomiting or poor feeding has caused dehydration, which can worsen the metabolic crisis.
Nutritional intake review – A careful manual review of what the patient has been eating or not eating helps identify high-protein intake or fasting, which can trigger attacks in citrullinemia type I.
Lab and pathological tests
Plasma ammonia level – This is one of the most important tests. Very high ammonia in the blood strongly suggests a urea cycle disorder such as citrullinemia type I and needs urgent treatment.
Plasma amino acid profile (including citrulline) – A special blood test (often tandem mass spectrometry) measures amino acids and shows very high citrulline levels in citrullinemia type I, which helps point to ASS1 deficiency.
Newborn screening test – In many countries, a heel-prick blood spot from newborns is tested for high citrulline as part of standard screening, so citrullinemia type I can be found before serious symptoms start.
Blood gas and acid-base tests – Arterial or venous blood gas shows pH, carbon dioxide, and bicarbonate levels, which help doctors see how the body is coping with the metabolic stress and whether there is respiratory or metabolic imbalance.
Liver function tests (AST, ALT, bilirubin) – These blood tests check how well the liver is working and can show liver stress or damage, which can be seen in some patients with citrullinemia type I.
Serum electrolytes and glucose – Measuring sodium, potassium, chloride, bicarbonate, and blood sugar helps rule out other causes of illness and guides safe treatment during a metabolic crisis.
Urine organic acids and orotic acid – Urine tests may show increased orotic acid or other substances that help distinguish different urea cycle disorders and confirm that the problem is in the ASS1 step.
ASS1 enzyme activity assay – In some centers, enzyme function can be measured in liver cells or skin fibroblasts to show that argininosuccinate synthetase activity is low or absent.
Molecular genetic testing of ASS1 – DNA testing looks for disease-causing mutations in the ASS1 gene and confirms the diagnosis, helps with carrier testing in relatives, and allows prenatal diagnosis in future pregnancies.
Pathology in severe or research cases – In rare situations, liver biopsy or post-mortem tissue studies may be used for research or complex cases to better understand the enzyme defect and liver changes, though this is not routine.
Electrodiagnostic tests
Electroencephalogram (EEG) – EEG records the brain’s electrical activity and is used when a patient with citrullinemia type I has seizures or altered consciousness, helping doctors see how much the brain is affected and rule out other causes.
Nerve conduction studies / EMG (in selected cases) – In chronic cases with muscle problems, nerve and muscle tests can see if there is damage from repeated hyperammonemia, although these tests are not needed for every patient.
Imaging tests
Brain MRI – Magnetic resonance imaging can show brain swelling, changes in the white matter, or other signs of injury from past high ammonia episodes, giving a picture of long-term damage.
Brain CT scan – In emergencies, a CT scan of the head can quickly detect severe brain swelling or bleeding in a patient who is unconscious or having seizures.
Cranial ultrasound in newborns – For very sick newborns, ultrasound through the soft spot on the skull can give early clues of brain swelling when MRI or CT is not yet possible.
Abdominal ultrasound – Ultrasound of the abdomen can show liver size and structure, and can help rule out other liver diseases that might look similar clinically.
Follow-up imaging for long-term damage – Over time, repeated MRI scans may be used to follow any brain injury and guide long-term care, such as therapies for developmental delay.
Non-pharmacological treatments
1. Strict protein-controlled diet
A carefully planned low-protein diet is the main non-drug treatment for citrullinemia type I. The goal is to limit protein just enough to reduce ammonia while still allowing normal growth. A metabolic dietitian calculates daily protein based on weight, age, and lab results. Special low-protein foods are often used to replace regular bread, pasta, or rice. This diet lowers the amount of nitrogen that enters the urea cycle, so less ammonia is produced in the body.
2. High-calorie, protein-free energy (carbohydrates and fats)
Patients are encouraged to take enough calories from carbohydrates (like glucose drinks) and fats to prevent the body from breaking down its own muscle for energy. When the body uses muscle, extra ammonia is released. Extra calories from protein-free formulas, special drinks, or tube feeds help keep the body in an “anabolic” state, meaning it is building or maintaining tissue instead of breaking it down. This reduces ammonia production and protects the brain, especially during illness or stress.
3. Emergency “sick-day” protocol
Families receive an emergency plan to follow when the child is sick, vomiting, or not eating. The plan usually includes stopping protein, giving extra glucose drinks or special emergency formulas, and going quickly to the hospital if feeding is poor. The purpose is to prevent a sudden rise in ammonia during infection or fasting. The mechanism is simple: less protein in, more calories in, and faster medical care lead to less protein breakdown and lower ammonia levels.
4. Avoidance of prolonged fasting
Long gaps without food make the body burn fat and muscle for energy, which releases amino acids and nitrogen. In citrullinemia type I this quickly raises ammonia. Parents are taught to avoid long overnight fasting and to give small frequent meals or night-time feeds. Before surgery or medical procedures, patients may receive intravenous glucose to bridge the fasting time. This strategy keeps the metabolism stable and reduces the risk of hyperammonemic crises.
5. Specialized medical formulas
Many patients use prescription medical formulas that contain essential amino acids in a controlled pattern and extra calories. These products allow safe protein intake without extra nitrogen from non-essential amino acids. The purpose is to support growth while limiting substances that stress the faulty urea cycle. The mechanism involves adjusting the amino acid profile to reduce production of ammonia and to balance nutrients that are low because of the restricted natural-protein diet.
6. Continuous nasogastric or gastrostomy tube feeding
Some infants and children cannot drink enough or need very precise nutrition. A soft tube through the nose or a small gastrostomy tube in the stomach can deliver formula around the clock. Slow continuous feeding avoids large protein loads at one time and reduces fasting periods. This method helps keep ammonia levels more stable and supports good growth and development when oral intake is unreliable.
7. Intravenous glucose infusion during acute illness
In hospital, 10% glucose with electrolytes is often given through a vein when a patient is not eating, vomiting, or is too sleepy. The purpose is to provide quick energy and stop muscle breakdown. Mechanistically, continuous glucose infusion stimulates insulin release and shifts metabolism toward using sugar instead of protein, which lowers ammonia production and protects the brain during hyperammonemic crises.
8. Intravenous lipid (fat) support
When longer-term intravenous feeding is needed, lipid emulsions are added to provide extra calories without adding nitrogen. By supplying energy from fat directly into the bloodstream, doctors can further reduce the need for the body to break down its own tissues. This helps stabilize ammonia levels while the intestines rest or while oral intake is unsafe.
9. Hemodialysis or continuous hemofiltration for severe hyperammonemia
In life-threatening situations with very high ammonia, emergency hemodialysis or continuous venovenous hemofiltration is used. A machine filters the blood and rapidly removes ammonia and nitrogen-containing waste products. The purpose is to lower ammonia as fast as possible to prevent brain swelling and permanent damage. Dialysis does not correct the enzyme defect, but it buys time while other treatments and diet changes take effect.
10. Intensive care monitoring and brain protection
During acute crises, patients may be cared for in an intensive care unit with close monitoring of vital signs, intracranial pressure, and blood chemistry. Sedation, ventilation support, and careful fluid control can be needed if there are seizures or coma. The goal is to reduce brain swelling and maintain oxygenation and blood flow. These supportive steps help limit secondary brain injury while ammonia is being cleared.
11. Developmental, speech, and physical therapy
Many children with repeated hyperammonemic episodes have developmental delays, learning difficulties, or movement problems. Early referral to speech therapy, occupational therapy, and physiotherapy can improve communication, fine motor skills, and muscle strength. The mechanism is neuro-rehabilitation: structured exercises and stimulation help the brain build alternative pathways and maximize function, even after early brain injury.
12. Psychological and educational support
Living with a chronic metabolic disease is stressful for the child and family. Psychological counseling, school support plans, and social work input can reduce anxiety and improve adherence to diet and medications. Good mental health care improves sleep, appetite, and cooperation with treatment. This indirectly stabilizes metabolic control, because stress and poor adherence can trigger ammonia rises.
13. Genetic counseling for the family
Citrullinemia type I is usually inherited in an autosomal recessive pattern. Genetic counseling explains carrier status, recurrence risks, and options like prenatal or preimplantation genetic testing. The purpose is informed family planning and early diagnosis in future pregnancies. Mechanistically, by identifying at-risk fetuses or newborns, doctors can start treatment before ammonia rises and prevent severe brain damage.
14. Newborn screening and early follow-up
In many regions, citrullinemia type I can be detected by routine newborn blood spot screening. Babies with abnormal results are called back for confirmatory tests and immediate metabolic care. Detecting the disease before symptoms allows early diet, medicines, and education. This dramatically lowers the chance of catastrophic hyperammonemic coma in the first days of life.
15. Infection prevention and vaccination
Infections commonly trigger metabolic decompensation. Staying up to date with routine vaccines and practicing good hand hygiene reduces the number of infections and therefore the number of high-ammonia episodes. Fewer infections mean fewer hospitalizations and more stable brain function over time. Vaccination works by training the immune system to recognize germs early, so the body clears them more quickly and with less fever and catabolism.
16. Temperature and stress management
High fever and strong physical or emotional stress can increase metabolic demands. Parents are advised to treat fever early with safe antipyretics prescribed by the doctor and to avoid extreme exertion or stress. The mechanism is to reduce the body’s need to break down extra protein during stressful events, helping to maintain stable ammonia levels.
17. School and workplace accommodations
Older children and adults may need flexible schedules, access to snacks, and permission for medical appointments. Teachers or employers can be informed about warning signs like confusion or extreme tiredness. These accommodations reduce pressure, prevent missed meals, and support quick response if symptoms of high ammonia appear, helping to maintain long-term cognitive and social function.
18. Medical alert identification
Wearing a medical alert bracelet or carrying an emergency information card tells paramedics and emergency doctors that the person has a urea-cycle disorder. This speeds up correct treatment, such as avoiding high-protein fluids and starting ammonia-lowering therapy quickly. Rapid recognition is critical because brain injury can occur within hours if high ammonia is not treated.
19. Home ammonia and symptom monitoring (where available)
In some centers, families may monitor symptoms closely and sometimes use point-of-care tests for ammonia or related markers. Even without home devices, keeping a diary of headaches, vomiting, behavior changes, and diet helps doctors adjust treatment. Early noticing of subtle changes allows faster intervention before severe hyperammonemia develops.
20. Participation in patient support groups
Joining rare-disease or urea-cycle disorder support groups connects families with others facing the same condition. Sharing experiences, practical tips, and emotional support can improve coping and adherence to complex treatment plans. Better understanding of the disease through group education often leads to safer daily choices, fewer crises, and better quality of life.
Drug treatments
Important: Drug names, classes, and typical doses below are based on regulatory labels and expert guidelines, but real dosing is always individualized by a metabolic specialist. Never change or start medicines without your doctor.
1. Glycerol phenylbutyrate (Ravicti)
Ravicti is an oral nitrogen-binding agent used for chronic management of urea-cycle disorders, including citrullinemia type I, in patients who cannot be controlled with diet alone. It is taken several times per day with food, and the dose is set by body size and ammonia levels. In the intestine, it is broken down to phenylbutyrate and then to phenylacetate, which combines with glutamine to form phenylacetylglutamine, a compound excreted in urine that removes waste nitrogen and lowers ammonia. Common side effects include stomach discomfort, diarrhea, and headache.
2. Sodium phenylbutyrate tablets (Buphenyl)
Buphenyl tablets are another nitrogen-scavenger medicine for chronic treatment of urea-cycle disorders. They are usually taken in multiple divided doses with meals. The typical daily dose in children and adults is calculated per kilogram or per square meter of body surface. Like Ravicti, sodium phenylbutyrate is converted to phenylacetate, which binds glutamine and carries nitrogen out of the body in urine. It must not be used for sudden, acute hyperammonemia. Side effects can include loss of appetite, menstrual changes, edema, and taste changes, and the sodium load may be a problem in heart or kidney disease.
3. Sodium phenylbutyrate oral pellets (Pheburane)
Pheburane is a taste-masked sodium phenylbutyrate formulation, often easier for children to swallow. Dosing is similar to other phenylbutyrate products and is measured using a dedicated spoon. It is used together with protein-restricted diet and sometimes amino acid supplements like arginine or citrulline. The drug’s mechanism again relies on binding glutamine to remove nitrogen as phenylacetylglutamine in urine. Side effects are similar to other phenylbutyrate products and may include gastrointestinal upset and high sodium exposure.
4. Sodium phenylacetate and sodium benzoate injection (Ammonul)
Ammonul is an intravenous combination of sodium phenylacetate and sodium benzoate used for acute treatment of high ammonia in urea-cycle disorders. It is given through a central vein using a carefully controlled infusion protocol, often together with dialysis and other emergency care. Phenylacetate binds glutamine and benzoate binds glycine, forming compounds excreted in urine to remove nitrogen quickly. Side effects include nausea, vomiting, metabolic acidosis, and risk from the high sodium load, so patients must be monitored in hospital.
5. Sodium benzoate (supportive nitrogen scavenger)
Sodium benzoate can be given orally or intravenously (as part of combination products) to bind glycine and form hippurate, which is then excreted by the kidneys, removing one nitrogen atom per molecule. In citrullinemia type I it may be used in acute and chronic settings under specialist care. Dosing is weight-based and must avoid toxicity. Side effects can include nausea, vomiting, and electrolyte disturbances, so frequent blood tests are required.
6. L-arginine supplementation
L-arginine is often prescribed as an oral or intravenous amino acid. In distal urea-cycle disorders, including citrullinemia type I, arginine becomes essential because the urea cycle is blocked. Giving arginine provides substrate for protein synthesis and helps drive alternative pathways for nitrogen excretion by promoting argininosuccinate formation, which can be excreted in urine. Dosing depends on age and clinical status. Side effects may include gastrointestinal upset or high potassium, so monitoring is needed.
7. L-citrulline supplementation
L-citrulline can also be used as a supplement in some urea-cycle disorders to support arginine levels and protein synthesis. In citrullinemia type I its role is more individualized because citrulline levels are already high, but it may be used in certain phases or for specific metabolic goals under expert guidance. It participates in the urea cycle and helps maintain nitric-oxide related functions. Side effects are usually mild gastrointestinal symptoms.
8. Carglumic acid (Carbaglu, N-carbamyl-L-glutamate)
Carglumic acid is a structural analogue of N-acetylglutamate and activates carbamoyl phosphate synthetase 1 (CPS1), the first enzyme in the urea cycle. It is officially approved for NAGS deficiency but is sometimes used off-label in other hyperammonemic states under expert protocols. Tablets are dispersed in water and given orally, with doses calculated per kilogram. By activating CPS1, carglumic acid can increase ammonia detoxification into urea. Reported side effects include vomiting, abdominal pain, and possible changes in liver enzymes, so close monitoring is required.
9. Intravenous dextrose solutions (e.g., 10% glucose)
Although not disease-specific, IV dextrose is treated as a “metabolic drug” in acute management. It is infused at high rates to provide energy and to stimulate insulin, which suppresses protein breakdown. The dosage is carefully titrated to maintain normal blood sugar while preventing fluid overload. Side effects can include hyperglycemia, electrolyte imbalance, and vein irritation. Its main mechanism is metabolic stabilization, helping other ammonia-lowering treatments to work more safely.
10. Intravenous lipid emulsions
IV lipid emulsions supply calorie-dense fat without adding nitrogen. They are often used in total parenteral nutrition when patients cannot eat. Dosing is based on grams of fat per kilogram per day and is increased gradually. The purpose is to prevent catabolism and protect the liver and muscles. Side effects may include high triglycerides, liver stress, or allergic reactions, so regular lab monitoring is needed.
11. L-carnitine
Carnitine helps transport long-chain fatty acids into mitochondria for energy production and may support energy metabolism in hyperammonemic patients. It is sometimes given orally or intravenously, especially when secondary carnitine deficiency or valproate use is present. The mechanism is improved fatty-acid oxidation and potential reduction of toxic metabolites. Side effects can include diarrhea and a fishy body odor at high doses. Use in citrullinemia type I is supportive and individualized.
12. Antiepileptic medicines (e.g., levetiracetam)
Severe hyperammonemia can cause seizures, and standard antiepileptic drugs may be required. Levetiracetam is often preferred because it has a relatively low interaction profile and can be given intravenously or orally. The goal is to control seizures and prevent further brain injury. It does not treat the metabolic defect but protects neurons while ammonia is being lowered. Dosing is based on weight, and side effects may include sleepiness or mood changes.
13. Anti-emetic medicines for vomiting
During crises, nausea and vomiting make it hard to take oral medicines or feeds. Carefully chosen anti-emetics can reduce vomiting, allowing better intake of glucose and nitrogen-scavenger drugs. The purpose is purely supportive: keeping oral therapy in place and preventing dehydration. Doctors choose agents that are safe for children and avoid drugs that worsen mental status. Side effects depend on the specific medicine but may include drowsiness or constipation.
14. Proton-pump inhibitors or H2 blockers
Patients on long-term nitrogen scavengers and high-calorie feeds may develop reflux or gastritis. Acid-reducing medicines can improve comfort and reduce vomiting, indirectly supporting metabolic control. Their mechanism is decreasing acid production in the stomach. Side effects can include diarrhea, constipation, or, with long-term use, nutrient malabsorption, so doctors balance risks and benefits.
15. Standard antibiotics during infections
Infections are dangerous triggers for hyperammonemia. Appropriate antibiotics (chosen based on site of infection and local guidelines) treat the underlying cause of fever and catabolism. By clearing infection, these drugs decrease metabolic stress and help stabilize ammonia. Doses and durations follow standard pediatric or adult recommendations, and side effects depend on the antibiotic class.
16. Intravenous fluids with electrolytes (maintenance solutions)
Balanced IV fluids maintain hydration and correct electrolyte disturbances during crises. The purpose is to support circulation, kidney function, and safe excretion of nitrogen-binding drug conjugates. The mechanism is simple replacement of water and salts lost through vomiting or dialysis. Over- or under-hydration can worsen brain swelling, so fluids are adjusted carefully using frequent lab checks.
17. Vitamin and trace-element supplements (medical formulations)
Because of strict diet and specialized formulas, patients may lack micronutrients like zinc, selenium, or certain vitamins. Medical multivitamin and mineral preparations correct these gaps. Adequate micronutrients support liver function, immunity, and growth, which indirectly help metabolic stability. Doses are usually within recommended daily allowances but tailored by blood tests.
18. Analgesics (paracetamol/acetaminophen under guidance)
Pain and discomfort raise stress hormones and can worsen catabolism. Carefully dosed paracetamol (acetaminophen) is often used for fever and pain relief, as it does not interfere directly with the urea cycle when used correctly. The mechanism is central pain and fever control. Overdose, however, can damage the liver, so exact dosing by weight and medical supervision are critical.
19. Sedatives and anesthetic agents (for procedures)
When patients need central lines, dialysis, or transplant surgery, controlled sedation or anesthesia is required. Agents are chosen to minimize metabolic disturbance and to allow safe completion of life-saving procedures. These medicines act on the brain to induce sleep and pain relief. Close monitoring avoids low blood pressure or breathing problems.
20. Post-transplant immunosuppressive drugs
After liver transplantation, patients must take immunosuppressive drugs such as tacrolimus or cyclosporine to prevent rejection of the new liver. In citrullinemia type I, a successful transplant can normalize the urea cycle, but lifelong immunosuppression is required. These drugs work by dampening T-cell activity. Side effects can include infection risk, high blood pressure, and kidney problems, so regular monitoring is essential.
Dietary molecular supplements
1. Essential amino-acid mixtures
Special essential amino-acid supplements provide the building blocks needed for growth without adding extra non-essential amino acids that increase nitrogen load. They are usually taken several times a day mixed into formula or food. By adjusting the amino-acid profile, these supplements support muscle and brain development while reducing ammonia production from unnecessary amino acids.
2. Branched-chain amino acids (BCAA) blends
BCAA mixtures (leucine, isoleucine, valine) may be included in medical formulas to support muscle protein synthesis in a controlled way. They are given according to dietitian plans. The mechanism is stimulation of muscle building and energy metabolism without overloading the urea cycle with nitrogen from other amino acids.
3. Arginine medical-grade powder
Medical-grade arginine powder, different from casual sports supplements, is measured precisely and added to formula. In citrullinemia type I, arginine helps maintain protein synthesis and supports alternative pathways for nitrogen removal through argininosuccinate excretion. Correct dosing is essential to avoid electrolyte disturbances.
4. Specialized carbohydrate polymers
Glucose polymers or maltodextrin powders provide concentrated carbohydrates that can be mixed into drinks or formula. They deliver energy without protein, helping to prevent catabolism and hyperammonemia. The mechanism is simple: more safe calories reduce the need for the body to break down muscle during illness or growth spurts.
5. Medium-chain triglyceride (MCT) oil
MCT oil is more easily absorbed and rapidly used for energy than long-chain fats. It can be added to feeds to increase calorie density without increasing protein. Better energy supply reduces muscle breakdown and stabilizes ammonia levels. It must be introduced slowly to avoid diarrhea or stomach upset.
6. Omega-3 fatty acid supplements
Omega-3 supplements can support cardiovascular and anti-inflammatory health in patients on high-fat or long-term specialized diets. While they do not directly affect the urea cycle, they may help overall organ health and brain function. Their mechanism is modulation of cell membranes and inflammatory signaling pathways.
7. Micronutrient blends (zinc, selenium, copper)
Balanced trace-element supplements correct deficiencies caused by restricted natural food choices. Proper levels of zinc and selenium support immunity and antioxidant defenses, which can protect against infections and oxidative stress during metabolic crises. Doses are carefully matched to lab results to avoid toxicity.
8. Fat-soluble vitamins (A, D, E, K) in controlled doses
Some patients need extra fat-soluble vitamins because of specialized diets or prolonged TPN. These vitamins support bone health, immunity, and clotting. The mechanism is restoration of normal biochemical pathways that rely on vitamin cofactors. Because they can build up in the body, dosing is carefully controlled and monitored.
9. Water-soluble vitamins (B-complex, C)
B-vitamins act as co-enzymes in many metabolic reactions, and vitamin C supports connective tissue and immune health. Supplementation ensures that tight dietary restrictions do not cause new deficiencies. By keeping these pathways efficient, the body can use energy and protein more effectively, indirectly supporting ammonia control.
10. Probiotic preparations
Some centers use probiotics to support gut health, especially when frequent antibiotics are needed. A healthier gut microbiome may reduce production of ammonia by intestinal bacteria and improve bowel habits. The evidence is still developing, so probiotics are considered an adjunct, not a main therapy.
Immune, regenerative and experimental therapies
1. Standard vaccination and immune support
Routine immunization according to national schedules is one of the safest “immune boosters” for patients with citrullinemia type I. Vaccines train the immune system to fight infections efficiently, reducing fevers and metabolic stress that can trigger ammonia spikes. Nutritious diet, sleep, and prompt infection treatment are more effective than unproven immune supplements.
2. Post-transplant immunosuppressive regimens
After liver transplantation, immunosuppressive drug combinations protect the transplanted liver from rejection. A healthy donor liver provides normal ASS1 enzyme activity and can essentially cure the urea-cycle defect. The “regenerative” effect comes from the new organ’s ability to detoxify ammonia normally, but this benefit requires lifelong immune-modulating therapy and careful monitoring.
3. Investigational AAV-based gene therapy
Research studies are testing adeno-associated virus (AAV) vectors delivering a working ASS1 gene directly to the liver. Early pre-clinical and clinical data suggest that gene therapy might restore urea-cycle function and reduce or remove the need for chronic nitrogen-scavenger drugs. These treatments are experimental, available only in controlled clinical trials, and long-term safety is still being studied.
4. Experimental cell-based or stem-cell approaches
Some research groups have explored cell-based therapies, such as transplanting hepatocyte-like cells derived from stem cells to partially replace faulty liver cells. The idea is to introduce enough healthy ASS1-expressing cells to improve ammonia detoxification. These strategies remain experimental and are not standard care. They should only be considered within approved research programs.
5. Antioxidant and mitochondrial support strategies
Because repeated hyperammonemia can damage mitochondria and generate oxidative stress, clinicians sometimes consider antioxidant strategies (for example, N-acetylcysteine or certain vitamins) as part of broader care. Evidence is limited, so these are supportive rather than disease-modifying. Their proposed mechanism is reducing oxidative injury in brain and liver cells exposed to ammonia.
6. Structured exercise rehabilitation after stabilization
Once metabolic control is stable, supervised moderate exercise programs can support muscle strength, bone health, and overall wellbeing. Exercise must be carefully paced and combined with proper pre- and post-activity snacks to avoid catabolism. The regenerative aspect comes from improved physical reserve and cardiovascular fitness, which help patients tolerate illness and stress better.
Surgeries and procedures
1. Orthotopic liver transplantation
Liver transplant replaces the patient’s diseased liver with a donor organ that has normal ASS1 enzyme activity. It is currently the only established curative treatment for citrullinemia type I. The procedure is recommended for patients with severe, recurrent hyperammonemic crises or neurological damage despite optimal medical therapy. After transplant, the urea cycle can function normally, which prevents further hyperammonemic attacks, although lifelong immunosuppression is needed.
2. Living donor liver transplantation
In regions with low deceased-donor organ availability, a relative may donate part of their liver. The partial graft can grow in the recipient and provide enough enzyme activity for ammonia detoxification. The reason for this surgery is to shorten wait time and reduce risk of brain damage while on the transplant list. Risks include surgical complications for both donor and recipient.
3. Central venous catheter placement for dialysis and infusions
For emergency dialysis or repeated intravenous nitrogen-scavenger therapy, a central venous catheter (CVC) is often inserted. This procedure allows high-flow access for hemodialysis and safe delivery of concentrated drugs. It is done when peripheral veins are not adequate, especially in infants. Risks include infection and blood clots, so careful line care is essential.
4. Gastrostomy tube (G-tube) insertion
A gastrostomy tube is placed surgically or endoscopically through the abdominal wall into the stomach. It allows reliable delivery of medical formula, medications, and emergency feeds. This procedure is done when oral intake is insufficient or when precise, frequent feeding is needed to maintain metabolic stability and growth.
5. Dialysis access surgery (peritoneal catheter or AV access)
For patients who may need repeated dialysis, surgeons can place a peritoneal dialysis catheter or create vascular access. The purpose is to allow rapid initiation of dialysis when ammonia rises dangerously. Dialysis removes ammonia and drug conjugates from the blood, protecting the brain during severe crises.
Prevention and long-term self-care
Newborn screening and early diagnosis – ensuring babies are tested and, if positive, seen quickly by a metabolic team prevents early crises.
Consistent follow-up with a metabolic center – regular visits allow dose changes and diet adjustments before problems appear.
Adhering strictly to prescribed diet and medicines – skipping nitrogen scavengers or diet rules is a major cause of avoidable crises.
Rapid treatment of infections and fever – contacting doctors early for antibiotics or hospital review reduces metabolic stress.
Avoidance of unnecessary high-protein loads – very high-protein diets, bodybuilding supplements, or certain IV solutions can be dangerous.
Planning ahead for surgery, fasting, or travel – pre-arranged hospital protocols, extra formula, and letters for airlines or schools improve safety.
Education of caregivers, schools, and emergency services – more people knowing the condition and its emergency steps means faster response in a crisis.
Genetic counseling before future pregnancies – parents can discuss options to identify affected babies early or to use reproductive technologies.
Healthy general lifestyle – enough sleep, moderate exercise, and stress management support overall metabolic stability.
Participation in research and registries – joining registries improves knowledge about the disease and may provide access to new treatments.
When to see doctors or go to emergency care
People with citrullinemia type I should contact their metabolic team urgently or go to an emergency department if there is vomiting, refusal to eat, unusual sleepiness, confusion, personality change, abnormal behavior, poor coordination, seizures, or loss of consciousness. Any infection with high fever, especially if oral intake is poor, is also an emergency. Newborns with poor feeding, breathing problems, or unexplained coma need immediate ammonia testing. Caregivers should bring the written emergency protocol and all medicines to hospital so treatment can start within hours, not days.
Diet: what to eat and what to avoid
1. Eat: prescribed amount of natural protein from foods like measured portions of milk, yogurt, eggs, or meat, as allowed by the dietitian.
2. Eat: special low-protein bread, pasta, and rice products to provide calories without much nitrogen.
3. Eat: plenty of allowed fruits and many vegetables (following any specific potassium or fiber advice) to supply vitamins and fiber.
4. Eat: medical formulas and essential amino-acid mixtures exactly as prescribed, as they replace ordinary protein sources.
5. Eat: frequent small meals and snacks to avoid long fasting periods.
6. Avoid: high-protein “all-you-can-eat” meals, protein shakes, bodybuilding powders, and high-protein fad diets.
7. Avoid: skipping prescribed formula or nitrogen-scavenger medicines, even on “good days.”
8. Avoid: unplanned fasting for weight loss or religious events without discussing adjustments with the metabolic team.
9. Avoid: over-the-counter herbal “protein boosters” or unknown supplements that may contain hidden amino acids.
10. Avoid: alcohol in older patients, because it stresses the liver and can worsen metabolic control.
Frequently asked questions
1. Is citrullinemia type I curable?
Medical therapy and diet can control citrullinemia type I but do not fix the genetic cause. Orthotopic liver transplantation can provide a permanent source of normal enzyme and is considered functionally curative for the urea-cycle defect, though lifelong immunosuppressive medicine is then required.
2. Can my child live a normal life span?
With early diagnosis, careful diet, regular medicines, and rapid treatment of crises, many people with citrullinemia type I can reach adulthood and live for many years. Outcomes are best when major hyperammonemic episodes are prevented or treated very quickly, especially in infancy.
3. Why is ammonia so dangerous?
Ammonia easily crosses into the brain and interferes with energy production, neurotransmitters, and water balance in brain cells. Very high levels cause swelling (edema), seizures, and coma, and can lead to permanent brain injury or death if not treated fast.
4. Will my other children have the disease?
Citrullinemia type I is autosomal recessive. When both parents are carriers, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier, and 25% chance of an unaffected non-carrier. Genetic testing and counseling can clarify risks for each family.
5. Can citrullinemia type I be found before birth?
Yes. If the family mutation is known, prenatal genetic testing or preimplantation genetic diagnosis may be discussed. These techniques help identify affected fetuses or embryos so families can plan care or consider options.
6. Why is the diet so strict?
Because the urea cycle is partly blocked, even normal amounts of protein can generate more ammonia than the body can handle. The diet limits total protein and uses special formulas so that growth needs are met while nitrogen load stays as low as safely possible.
7. Will my child always need nitrogen-scavenger drugs?
Most patients require long-term nitrogen-binding medicines alongside diet, especially those with more severe enzyme deficiency. The exact drug and dose can change with age, size, and clinical stability. Some transplanted patients may eventually stop these drugs, after specialist approval.
8. Are sports and exercise allowed?
Light to moderate exercise is usually encouraged once metabolic control is stable, but very intense, prolonged exercise may be risky because it increases protein breakdown. Plans should be made with the metabolic team, and extra snacks are often recommended around activity.
9. Can infections always be prevented?
No, but good hygiene, vaccinations, and early medical review can greatly reduce the number and severity of infections. This, in turn, lowers the risk of hyperammonemic episodes and hospital admissions.
10. Is gene therapy available now?
Gene therapy for citrullinemia type I is still in the research stage. Some clinical trials use viral vectors to deliver a healthy ASS1 gene to the liver, but these treatments are not yet standard care and are available only in specialized research programs with strict safety monitoring.
11. What happens if we miss a dose of medicine?
Missing a single dose may not cause immediate problems, but repeated missed doses increase ammonia risk over time. If a dose is forgotten, families should follow the specific instructions from their metabolic team and avoid double-dosing without guidance.
12. Can over-the-counter protein or herbal “boosters” be used?
No. Many over-the-counter products contain hidden amino acids, nitrogen, or other substances that can worsen hyperammonemia or interact with medicines. Always check with the metabolic clinic before using any new supplement.
13. Does liver transplant remove all health risks?
Liver transplant dramatically reduces the risk of urea-cycle crises, but it introduces new long-term issues such as infection and cancer risk from immunosuppression and possible organ rejection. Patients need lifelong follow-up with transplant and metabolic teams.
14. What about pregnancy in women with citrullinemia type I?
Pregnancy is high risk but may be possible with close planning. Women need pre-pregnancy counseling, tight metabolic control, and coordinated care between metabolic specialists and high-risk obstetricians to prevent hyperammonemia during pregnancy and after delivery.
15. Where can families find more support?
Families can connect with national urea-cycle disorder foundations, rare-disease networks, and online support groups. These organizations offer education, advocacy, and peer support and sometimes link to clinical trials and expert centers.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 26, 2025.
