Argininosuccinate synthase 1–gene related citrullinemia type I is a rare, serious genetic disease of the urea cycle. In this disease the ASS1 gene does not work properly, so the enzyme argininosuccinate synthase is missing or too weak. Because of this, the body cannot remove extra nitrogen, and a toxic substance called ammonia builds up in the blood. This high ammonia level is called hyperammonemia and can quickly damage the brain and other organs, especially in newborn babies.
Argininosuccinate synthase-1 (ASS1)-gene related citrullinemia type I (often called CTLN1) is a rare inherited urea-cycle disorder where the liver enzyme ASS1 does not work properly or is missing. This enzyme normally helps turn waste nitrogen into urea, which is safely removed in urine. When ASS1 is missing, ammonia and citrulline build up in the blood, a condition called hyperammonemia, which can damage the brain, especially in babies and children.1
Citrullinemia type I is passed in an autosomal recessive pattern, which means a child must receive one non-working ASS1 gene from each parent. Some babies become very sick in the first days of life, with poor feeding, vomiting, sleepiness, seizures, or coma. Others may have a milder, later-onset form, with headaches, confusion, behavior changes, or learning problems if ammonia levels rise more slowly.1 2
Citrullinemia type I usually starts in the first few days after birth. The baby seems normal at first, then becomes very sleepy, refuses feeds, vomits, and may have seizures or coma if ammonia is very high. Some people have milder forms that appear later in childhood or adulthood, often during times of stress such as infection or a very high-protein meal. All these forms are caused by changes in the same ASS1 gene.
This condition is inherited in an autosomal recessive pattern. This means a child gets one changed (mutated) copy of the ASS1 gene from each parent. Parents usually have no symptoms, because they each still have one working copy of the gene. When both parents are carriers, each pregnancy has a 25% chance to result in a baby with citrullinemia type I.
Other names
Citrullinemia type I has several other names that you may see in reports or articles. These names all describe the same basic problem: a lack of the enzyme argininosuccinate synthase. Common other names include: “argininosuccinate synthase deficiency,” “ASS1 deficiency,” “argininosuccinic acid synthase deficiency,” “classic citrullinemia,” and “citrullinemia, classic (CTLN1).”
Types
Doctors now know that ASS1-related citrullinemia type I is not just one single pattern. The same gene problem can cause different clinical types. These types are usually described as:
Acute neonatal citrullinemia type I
This is the most classic and severe form. A baby with this type is born looking normal, but within the first few days of life they stop feeding well, vomit, become very sleepy, and may have seizures or coma. The ammonia in the blood is very high, and this is a medical emergency that needs fast hospital care.Mild later-onset citrullinemia type I
In this type the enzyme still has some activity. Symptoms may only appear in childhood, teenage years, or even adulthood. People may have repeated episodes of headache, confusion, vomiting, or behavior changes, often after illness, fasting, or a very high-protein meal. Between attacks they may feel almost normal.Asymptomatic biochemical form
Some people have high citrulline in the blood on newborn screening or other blood tests but have no clear symptoms, at least for many years. They still have ASS1 gene variants, so they are at risk of hyperammonemia if their body is under strong stress, and they still need follow-up and diet advice.Pregnancy-related citrullinemia type I
A few women with previously mild or unnoticed ASS1 deficiency only develop symptoms during pregnancy or soon after delivery. The physical stress of pregnancy, labor, and changes in protein metabolism can trigger sudden hyperammonemia with headache, confusion, or coma if not recognized.
Causes and risk factors
Biallelic ASS1 gene mutations
The main cause of citrullinemia type I is having two disease-causing changes (mutations) in the ASS1 gene, one from each parent. These mutations damage the structure or production of argininosuccinate synthase, so the urea cycle cannot complete its job of converting ammonia into urea for safe removal.Loss of argininosuccinate synthase enzyme activity
Because the gene is damaged, the enzyme argininosuccinate synthase in liver cells is very low or absent. This enzyme normally joins citrulline and aspartate to form argininosuccinic acid in the third step of the urea cycle. When this step fails, ammonia builds up in the blood.Autosomal recessive inheritance pattern
The autosomal recessive pattern itself is a cause, because it explains how the condition appears in families. Parents are healthy carriers but have a 25% chance in each pregnancy to have a child with citrullinemia type I. This pattern means brothers and sisters can also be affected or be carriers.Missense and other types of mutations in ASS1
Many different types of mutations have been reported, including missense (single amino acid change), nonsense (early stop), splice-site, and small deletions or insertions. All of them disturb the normal enzyme and can cause the disease. Some mutations cause severe neonatal disease; others allow milder, later-onset forms.Family history and consanguinity
Having parents who are related by blood (for example, cousins) raises the chance that both carry the same ASS1 mutation. In such families, more than one child with citrullinemia type I can be seen. A family history of unexplained newborn deaths or hyperammonemia also points to this cause.Urea cycle failure and ammonia build-up
The fundamental biochemical cause of symptoms is failure of the urea cycle to remove nitrogen waste. Ammonia builds up in the blood and brain, leading to swelling of brain cells (cerebral edema) and many neurological problems, including seizures and coma if not treated.High protein intake
Eating too much protein at one time can overload the broken urea cycle. In people with ASS1 deficiency, this can suddenly raise ammonia levels and trigger an acute attack with vomiting, confusion, or coma, even if they were previously well controlled on diet.Fasting and prolonged starvation
When a person fasts or eats very little, the body breaks down its own muscle protein for energy. This process releases extra nitrogen, which becomes ammonia. In urea cycle disorders like citrullinemia type I, this extra load can cause dangerous hyperammonemia.Fever and infections
Illness, especially with fever, makes the body catabolic, meaning it breaks down tissue proteins. This natural stress response increases ammonia production. In people with ASS1 deficiency, infection is a common trigger for hyperammonemic crises.Surgery and anesthesia
Operations and general anesthesia put the body under heavy stress. Protein breakdown and changes in metabolism can sharply increase ammonia levels in patients with urea cycle disorders, including citrullinemia type I, unless special precautions are taken.Dehydration and poor fluid intake
Dehydration can worsen hyperammonemia because the body has less fluid to carry waste products away and the kidneys work less well. Vomiting and poor feeding from the illness itself often make dehydration part of the problem in acute attacks.Extreme physical stress or trauma
Very hard exercise, accidents, or other major physical stress can increase protein breakdown and energy needs. This extra metabolic load can exceed the weak urea cycle capacity in someone with ASS1 mutations and cause a hyperammonemic episode.Pregnancy and childbirth
Pregnancy changes protein and nitrogen metabolism in complex ways. In women with mild or previously silent citrullinemia type I, pregnancy and the period just after birth can trigger hyperammonemia, sometimes with severe brain symptoms if not recognized early.Poor dietary control
Not following a prescribed low-protein diet or skipping special medical formulas and medications allows ammonia to rise slowly over time. This can lead to chronic problems like developmental delay or liver injury and can also set the stage for sudden acute crises.Delayed diagnosis or missed newborn screening
In places without newborn screening or when follow-up is missed, babies with citrullinemia type I may go unrecognized until they present with severe hyperammonemia. Late diagnosis means the first “cause” of brain injury is simply not knowing the child has this urea cycle defect.Intercurrent liver disease
Because the urea cycle works in the liver, additional liver problems, such as infections or toxins, may further reduce urea cycle capacity. In a person with ASS1 deficiency, this extra liver stress can worsen ammonia control.Certain medications
Some drugs can increase protein breakdown or affect liver function. In people with urea cycle disorders, such medicines can help trigger hyperammonemia. This is why all new drugs should be checked with a metabolic specialist in patients with citrullinemia type I.Gastrointestinal bleeding
Blood in the gut is broken down as if it were a protein meal. In people with urea cycle disorders, a large internal “protein load” from bleeding can raise ammonia to dangerous levels, even without extra food intake.Psychological stress and poor intake
Strong emotional stress may lead to poor eating, missed medication, or poor sleep. In people with citrullinemia type I, this can indirectly cause catabolism and raise ammonia levels, especially if it continues for several days.Lack of specialist follow-up and education
Without regular review by a metabolic team, families may not learn how to manage illness days, how to adjust protein intake, or when to seek urgent help. This lack of support becomes a practical cause of repeated hyperammonemic crises and long-term complications.
Symptoms and signs
Poor feeding and refusal to eat
One of the earliest signs in newborns is that the baby does not suck well, refuses the breast or bottle, or stops feeding after a few minutes. This happens because high ammonia makes the baby feel very unwell and sleepy, even before more serious symptoms appear.Vomiting
Many babies and older patients with citrullinemia type I vomit again and again during an attack. Vomiting is the body’s general response to being very sick and is common in hyperammonemia and urea cycle disorders.Lethargy (extreme sleepiness)
Babies may become unusually sleepy, floppy, and hard to wake. Older children or adults may feel very tired, confused, or “out of it.” This lethargy is a key sign that ammonia is affecting the brain.Irritability and behavior changes
Before becoming very sleepy, babies may be irritable, cry constantly, or seem uncomfortable. Older patients can show sudden behavior changes, mood swings, or confusion. These brain signs reflect early effects of ammonia toxicity.Seizures
Seizures are fits or convulsions that happen when brain cells are damaged or irritated. In citrullinemia type I, seizures often appear when ammonia is very high and the brain is swollen, and they are a serious warning sign of hyperammonemic encephalopathy.Loss of consciousness and coma
If hyperammonemia is not treated quickly, the patient can slip from sleepiness into unresponsiveness and coma. This means the brain is very swollen and is a life-threatening situation that needs intensive care and urgent ammonia-lowering treatment.Abnormal muscle tone (hypotonia or spasticity)
Some babies are very floppy (low tone), while others, especially later, may develop very tight muscles and stiffness (spasticity). These problems come from brain injury caused by repeated or very high ammonia levels.Breathing problems
Infants may breathe very fast or have trouble breathing. This can be a response to acidosis (too much acid in the blood) or brain swelling. In severe cases, they may need help with breathing in an intensive care unit.Hepatomegaly and liver problems
The liver may become enlarged, and blood tests can show liver injury. Over time some patients develop liver failure. The exact reasons are complex but are related to chronic metabolic stress on the liver and repeated hyperammonemia.Headache and migraine-like episodes
In milder, later-onset cases, patients may have repeated severe headaches, often with vomiting, visual changes, or ataxia (unsteady walking). These episodes often follow protein-rich meals or illness and reflect brain sensitivity to high ammonia.Ataxia and balance problems
Some older patients show unsteady walking, clumsiness, or difficulty with coordination during or after hyperammonemic episodes. This ataxia may improve when ammonia is controlled but can become long-lasting if brain injury occurs.Failure to thrive and poor growth
Without good metabolic control, children may not gain weight or height as expected. Poor appetite, vomiting, and strict protein limits can all affect growth, especially if diet is not carefully balanced with specialist help.Developmental delay and learning problems
Repeated or prolonged hyperammonemia can cause permanent damage to the developing brain. Children may be slow to reach milestones, have learning difficulties, or need special schooling, even if acute crises are later prevented.Psychiatric and cognitive symptoms in adults
Adults with later-onset or under-treated citrullinemia type I can show confusion, personality change, depression, or psychosis during attacks. These mental health symptoms can be mistaken for primary psychiatric disease if ammonia levels are not checked.Cerebral edema and signs of raised intracranial pressure
Very high ammonia can cause swelling of the brain (cerebral edema). This may lead to bulging fontanelle in infants, severe headache, vomiting, and sudden worsening of consciousness. Brain scans often show typical patterns of swelling and damage.
Diagnostic tests
(Grouped by type, but numbered in one list.)
General physical examination (physical exam)
The doctor carefully checks the baby or patient, looking at level of alertness, breathing pattern, color, hydration, and signs of liver disease. In a newborn with poor feeding, vomiting, and lethargy, this exam raises suspicion for a metabolic or urea cycle disorder like citrullinemia type I.Neurological examination (physical exam)
The clinician checks muscle tone, reflexes, pupil responses, and movements. Abnormal tone, seizures, or coma suggest the brain is affected by high ammonia, and this makes urgent metabolic and neurological tests essential.Growth and nutritional assessment (physical exam)
Measuring weight, length/height, and head size over time helps detect failure to thrive, growth delay, or microcephaly in long-standing cases. These findings support a chronic metabolic problem and guide diet planning in known citrullinemia type I.Abdominal examination for hepatomegaly (physical exam)
The doctor gently feels the abdomen to see if the liver is enlarged. An enlarged, firm liver may indicate liver involvement in citrullinemia type I or other urea cycle disorders and guides further liver tests and imaging.Bedside mental status check (manual test)
Simple bedside tests such as asking the patient their name, where they are, or to follow simple commands help the team judge brain function. Worsening confusion or inability to respond suggests rising ammonia and the need for emergency treatment.Manual assessment of muscle tone and reflexes (manual test)
The doctor moves the arms and legs and taps tendons to check tone and reflexes. Very floppy or very stiff muscles, or absent reflexes, are signs of serious brain involvement from hyperammonemia in citrullinemia type I.Manual coordination tests (manual test in older patients)
Older children and adults may be asked to touch their nose, walk in a straight line, or perform simple coordination tasks. Problems with these tasks can show ataxia or subtle brain damage from past or current ammonia elevation.Plasma ammonia level (lab/pathological test)
Measuring ammonia in the blood is the key test in suspected urea cycle disorders. In citrullinemia type I, ammonia is usually very high (often over 150 micromol/L) during attacks. This confirms hyperammonemia and helps guide urgent dialysis and drug treatment.Plasma amino acid profile with citrulline (lab/pathological test)
A detailed amino acid test usually shows very high citrulline levels in the blood in citrullinemia type I, often 50–100 times normal. Arginine is often low. This special pattern helps distinguish CTLN1 from other urea cycle disorders.Urine orotic acid measurement (lab/pathological test)
Many patients with citrullinemia type I have increased orotic acid in the urine. This happens because the blocked urea cycle pathway causes extra carbamoyl phosphate to be shunted into pyrimidine synthesis, forming orotic acid. The test supports the diagnosis alongside other findings.Liver function tests (lab/pathological test)
Blood tests such as ALT, AST, bilirubin, and clotting tests help show whether the liver is inflamed or failing. These tests are important because CTLN1 can cause liver disease or liver failure in some patients, especially if control is poor.Blood gas and acid–base status (lab/pathological test)
Measuring pH, carbon dioxide, and bicarbonate in blood helps detect acidosis, which often occurs in acute hyperammonemia. It also helps the care team judge breathing and circulation status and plan intensive care support.Newborn screening dried blood spot test (lab/pathological test)
In many countries, newborn screening programs include citrullinemia type I. A tiny blood spot from the baby’s heel is tested for high citrulline and other markers. Abnormal results prompt confirmatory testing and allow early treatment before severe symptoms appear.Targeted molecular genetic testing of ASS1 (lab/pathological test)
Sequencing the ASS1 gene in blood confirms the diagnosis by finding two pathogenic variants. This test is considered the gold standard to prove ASS1-related citrullinemia type I, to support carrier testing in relatives, and for prenatal diagnosis in future pregnancies.Enzyme activity assay in fibroblasts (lab/pathological test)
In some centers, a skin biopsy can be used to grow fibroblasts and directly measure argininosuccinate synthase activity. Very low or absent activity supports the diagnosis, especially when genetic testing is unclear or incomplete.Electroencephalogram (EEG) (electrodiagnostic test)
An EEG records electrical activity in the brain. In citrullinemia type I, EEG can show patterns of encephalopathy and seizures during hyperammonemic episodes. It helps monitor the brain and guide seizure treatment in the intensive care setting.Nerve conduction or evoked potential studies (electrodiagnostic test)
These tests are less common but can be used when there is concern about long-term neurological damage. They measure how well signals travel along nerves or sensory pathways and can show residual effects after severe hyperammonemic crises.Brain CT scan (imaging test)
A CT scan of the head can show cerebral edema (brain swelling), loss of normal brain structure, or other changes in hyperammonemic infants with CTLN1. These findings confirm that the brain is under severe stress and help rule out other causes of coma or seizures.Brain MRI (imaging test)
MRI gives more detailed pictures of the brain and often shows diffuse white-matter changes, ischemic-hemorrhagic lesions, or atrophy in citrullinemia type I. MRI is useful both in acute stages and for long-term follow-up of neurological injury.Liver ultrasound or other abdominal imaging (imaging test)
Ultrasound of the abdomen allows doctors to look at liver size and texture and to check for other abdominal problems. In CTLN1 it can show hepatomegaly or liver disease and helps in planning long-term management and considering liver transplant in selected cases.
Non-pharmacological treatments (therapies and other supports)
Note: In real life, your exact plan must be designed and adjusted only by a metabolic specialist and dietitian who know your ammonia levels, age, and overall health.
Protein-restricted, carefully planned diet
A controlled low-protein diet is the core non-drug treatment for citrullinemia type I. The diet limits natural protein (meat, fish, eggs, dairy, legumes) to reduce nitrogen load but still provides enough for growth and tissue repair. Calories come from carbohydrates and fats so that the body does not break down its own muscle, which would release more ammonia. The diet is always individualized and must be supervised by a metabolic dietitian.1 3Special medical formula (urea-cycle disorder formula)
Many patients use special medical formulas that are low in total protein but enriched with essential amino acids and calorie sources. These formulas are designed to support normal growth while limiting nitrogen. They are usually given in measured amounts across the day. The purpose is to replace regular milk or high-protein drinks with a safer alternative that matches the patient’s tolerance.3 4Frequent meals and avoidance of fasting
Long gaps without food force the body to break down its own muscle for energy, releasing amino acids and nitrogen. Frequent small meals and bedtime snacks, and sometimes continuous night feeds in young children, help keep the body in a “non-catabolic” state. This strategy reduces the risk of sudden ammonia spikes, especially during illness or after surgery.3 9Emergency “sick-day” management plan
Families receive a written emergency plan that explains what to do when the patient has fever, vomiting, poor intake, or stress. This often includes stopping protein, giving extra carbohydrate drinks or oral glucose polymer, and contacting the metabolic team or going to hospital early. The goal is to prevent a crisis rather than waiting until symptoms are severe.3 9Regular monitoring and clinic follow-up
Planned visits with a metabolic specialist include blood tests for ammonia, amino acids, liver function, and nutritional status. Growth, school performance, and behavior are also reviewed. Early detection of rising ammonia or nutritional deficiencies allows the team to adjust diet and medicines before major complications occur.1 4Genetic counseling for family members
Genetic counselors explain the autosomal recessive inheritance pattern, carrier testing, and options for prenatal or pre-implantation genetic diagnosis. This helps parents and extended family understand recurrence risks and make informed reproductive decisions. It also identifies other relatives who may be carriers.1 2Education for parents, patients, and schools
Clear teaching in simple language helps caregivers and older children recognize early warning signs like headache, vomiting, irritability, or unusual sleepiness. Schools and daycare centers learn about the condition, safe snacks, and when to contact parents or emergency services. This shared knowledge reduces delays in treatment during the day.1 3Written emergency letter or ID card
Many metabolic centers provide an emergency letter or wallet card that explains CTLN1, usual medications, and recommended emergency steps for doctors. Carrying this card helps emergency staff act quickly and avoid dangerous delays or inappropriate treatments when the patient arrives at a hospital that does not know them.9 1Developmental and neuropsychological support
Children with repeated hyperammonemia are at risk of learning difficulties, attention problems, or motor delay. Early developmental assessment and therapies (such as early childhood intervention and neuropsychology support) can improve skills, school performance, and quality of life. Individual education plans may be needed at school.1 4Physiotherapy and safe physical activity
Gentle, regular exercise supports muscle strength, bone health, and overall wellbeing. Physiotherapists can design activity programs that avoid extreme over-exertion or prolonged fasting before sport. Balanced activity may also support mental health and sleep quality in people living with chronic disorders.3 4Occupational therapy and daily-living support
Occupational therapists help children or adults with attention, coordination, or fatigue issues adapt daily tasks and school/work environments. They may recommend equipment, schedule breaks, or adjust writing and computer tasks so that individuals can participate more fully in education and work.4 1Speech and language therapy
If early brain injury affects speech or swallowing, a speech-language therapist can support safe feeding techniques, language development, and communication strategies. This improves social interaction and reduces the risk of aspiration or feeding difficulties.1 4Psychological counseling and family support
Living with a rare genetic disorder is stressful for patients, parents, and siblings. Counseling and support groups help families cope with anxiety, guilt, and fear of metabolic crises. Emotional support also improves adherence to complex treatment plans and long-term outcomes.1Vaccination and infection-prevention plans
Routine vaccines (and sometimes additional influenza or other recommended vaccines) help reduce infections that can trigger catabolism and hyperammonemia. Hand-washing, early treatment of fevers, and avoiding close contact with sick people are also important everyday infection-prevention strategies.3 9Pre-pregnancy counseling and planning for adults
Women with CTLN1 need careful planning before pregnancy. The metabolic team reviews diet, medications, and liver status, and creates a pregnancy and delivery plan to avoid hyperammonemia during labour or postpartum. This protects both mother and baby.1 3Telemedicine and remote monitoring
Telehealth visits can help families who live far from metabolic centers. Sharing lab results, food logs, and symptoms online allows faster adjustments to diet and medicines and reduces travel burden, while still keeping close professional oversight.3Structured transition to adult metabolic care
Teenagers with CTLN1 need support to move from pediatric to adult services. A planned transition program teaches self-management, understanding of their condition, and how to navigate adult clinics and insurance systems, reducing gaps in care.1Social work and financial counseling
Many families need help with insurance, disability benefits, and access to expensive formulas and medications. Social workers connect them with support programs and charities, helping maintain treatment adherence and reduce stress.1Lifestyle planning for travel and emergencies
Planning ahead for trips, school camps, and holidays includes carrying medicine, formula, emergency letters, and knowing the nearest hospital. This preparation helps reduce risk when routines change and access to usual food or pharmacy is limited.3Participation in patient-support organizations
Joining patient groups for urea-cycle disorders gives families education, emotional support, and shared practical tips. These organizations also help connect families with clinical trials and updated guidelines from expert centers.1
Drug treatments
Important safety note: Drug choices, doses, and timing must always be set by a metabolic specialist. Do not change any medicine based on online information alone.
Below are key medicines used in urea-cycle disorders, including ASS1-related citrullinemia type I. Many have detailed prescribing information on accessdata.fda.gov.
Sodium phenylbutyrate tablets (BUPHENYL®)
Sodium phenylbutyrate is a nitrogen-binding agent that joins with glutamine to form a compound excreted in urine, carrying away waste nitrogen and lowering ammonia.5 It is taken several times daily with food. Common side effects include taste changes, stomach upset, and menstrual irregularities; overdose or incorrect dosing can cause neurotoxicity.5Sodium phenylbutyrate powder (BUPHENYL®)
The powder form allows dose adjustment in infants and small children who cannot swallow tablets. It is mixed with food or liquid and taken in divided doses across the day.5 The mechanism and side effects are similar to the tablet form, and careful dosing based on body surface area is essential.5Sodium phenylbutyrate oral pellets (PHEBURANE®)
PHEBURANE is a taste-masked oral pellet form of sodium phenylbutyrate that improves palatability, especially in children.6 Pellets are sprinkled on soft food and swallowed without chewing. It works as a nitrogen-scavenging agent; adverse effects include gastrointestinal discomfort and odor, and exact dosing follows weight and previous ammonia levels.6Sodium phenylbutyrate for oral suspension (OLPRUVA™)
OLPRUVA is another sodium phenylbutyrate product approved as an oral suspension for long-term management of certain urea-cycle disorders.7 It is taken with meals in divided doses. The purpose is the same—binding nitrogen for excretion—and the label warns about neurological symptoms, metabolic acidosis, and electrolyte disturbances if dosing is excessive.7Glycerol phenylbutyrate oral liquid (RAVICTI®)
Glycerol phenylbutyrate is a pro-drug that is converted in the body to phenylbutyrate and then to phenylacetylglutamine, removing nitrogen in urine.8 It is given three times daily with meals. Common side effects include diarrhea, abdominal pain, gas, and fatigue; the label cautions about misuse in acute hyperammonemia.8Intravenous sodium phenylacetate and sodium benzoate (AMMONUL® or similar)
In acute crises, IV sodium benzoate and sodium phenylacetate may be used to rapidly remove nitrogen while dialysis is arranged.9 Benzoate conjugates with glycine and phenylacetate with glutamine, forming excretable compounds. Side effects include nausea, hypokalemia, and risk of circulatory overload, so close monitoring in intensive care is required.9Oral sodium benzoate
In some protocols, oral sodium benzoate is used as part of chronic nitrogen-scavenging therapy in selected patients.10 It joins with glycine to form hippurate, which is excreted in urine, reducing nitrogen. Side effects can include taste issues, fluid retention, and, rarely, metabolic acidosis, so dose and electrolytes must be checked regularly.10L-arginine (oral or intravenous)
Because ASS1 deficiency disrupts arginine production, L-arginine supplementation is often used to support the urea cycle, promote excretion of nitrogen as argininosuccinate, and correct plasma amino acid imbalances.3 It may be given orally every few hours or intravenously during crises. Side effects include hyperkalemia, vein irritation, and hypotension if given too fast.3L-citrulline (oral)
L-citrulline is sometimes used to modulate the urea cycle and amino acid profile, especially in milder or late-onset cases. It is converted in the body into arginine, supporting nitric oxide production and urea-cycle function. Doses and benefit vary, and it is usually combined with diet and other medicines. Gastrointestinal upset is the most common side effect.3Essential amino acid mixtures
Special essential amino acid blends, sometimes prescribed as “medical foods,” may be used to provide essential building blocks for growth while keeping total nitrogen intake within the safe limit.4 These mixtures are adjusted to each patient’s tolerance and taken several times per day, often combined with nitrogen-scavenging drugs and low-protein natural food.4Intravenous glucose (10–20%)
During acute hyperammonemia, IV glucose provides high-calorie, protein-free energy to stop the body from breaking down its own muscle. It is usually started immediately in hospital, sometimes with insulin to control blood sugar. Main risks are hyperglycemia and fluid overload, so monitoring is essential.9Intravenous lipid emulsions
IV lipids are sometimes added as extra calories in acute crises to further reduce catabolism and muscle breakdown.9 They must be used carefully in patients with liver dysfunction or pancreatitis. Side effects can include high triglycerides and infusion reactions, so they are usually used in intensive care under specialist guidance.9
(To stay within your requested word limit, the remaining supportive medicines — such as anti-emetics, antacids or proton-pump inhibitors for reflux, and carefully chosen anticonvulsants when seizures occur — are usually considered “helper” drugs rather than core ammonia-lowering therapies, and are selected individually by the treating team.)
Dietary molecular supplements
Always discuss supplements with your metabolic team; some “natural” products may contain hidden protein or interact with medicines.
L-arginine supplement
Oral L-arginine is often used like a “metabolic supplement” to support the urea cycle, encourage nitrogen excretion, and correct low arginine levels in ASS1 deficiency. It is usually given in multiple daily doses, mixed into formula or drinks. Over-supplementation can cause high potassium, low blood pressure, or GI upset, so blood levels and electrolytes must be checked.3L-citrulline supplement
L-citrulline can be taken as capsules or powder and is converted into arginine in the body. In some patients it helps stabilize amino acid profiles and may support nitric-oxide-related blood vessel function. It should be used only under specialist guidance because high doses can cause GI discomfort and may not be suitable in all urea-cycle disorders.3Essential amino acid (EAA) mixes
Commercial EAA mixes provide all essential amino acids in controlled amounts. In CTLN1 they are used to support growth while limiting total nitrogen intake from natural protein. Doses are calculated by the metabolic dietitian based on weight, age, and lab results. Taste and adherence can be challenging, so flavoring strategies are often used.4Branched-chain amino acids (BCAAs)
BCAAs (leucine, isoleucine, valine) may be adjusted within medical formulas to support muscle maintenance and reduce catabolism. They are not usually given separately as bodybuilding-type supplements because those products may contain excess protein or unknown ingredients. In CTLN1, changes in BCAA levels are managed as part of the overall amino-acid profile.4Omega-3 fatty acids (fish oil or algal oil)
Omega-3 supplements may support heart, brain, and anti-inflammatory health in chronic metabolic conditions. They provide calories without protein and can be useful if dietary fat is limited. However, high doses can affect bleeding risk or interact with other medicines, so the metabolic or primary-care team should approve the plan.3Medium-chain triglyceride (MCT) oil
MCT oil is a concentrated calorie source that is easier to absorb and oxidize than some long-chain fats. It helps supply energy without adding nitrogen. It can be mixed into formula or food in measured amounts. Too much may cause diarrhea or abdominal discomfort, so doses are increased slowly.3Vitamin D and calcium
Chronic dietary restriction and low dairy intake can increase risk of bone problems. Vitamin D and calcium supplements support bone mineralization and reduce fracture risk. Doses are individualized and guided by blood tests and sometimes bone-density scans. Excess vitamin D can cause high calcium and kidney issues, so monitoring is needed.4B-complex vitamins (including B6, B12, folate)
B-vitamins are involved in amino-acid metabolism and red-blood-cell formation. A balanced B-complex supplement may be advised if intake from natural foods is limited. Over-the-counter “mega-dose” products are usually not needed; instead, the dietitian chooses evidence-based doses based on lab results.4Zinc supplements
Zinc is important for growth, immune function, and wound healing. Low-protein diets can sometimes reduce zinc intake. A modest zinc supplement, adjusted to age and weight, may be recommended if blood tests show deficiency. Very high doses can interfere with copper levels, so medical supervision is essential.4Probiotics
Some clinicians consider probiotics as a supportive measure to maintain a healthy gut microbiome, which may indirectly influence nitrogen handling and immune function. Evidence in urea-cycle disorders is limited, so probiotics should be viewed as adjunctive, not core therapy, and should be selected carefully in patients with central lines or severe immune issues.3
Immunity-boosting, regenerative, and stem-cell–related approaches
At present, there are no widely approved “stem cell drugs” specifically for ASS1-related citrullinemia type I. The options below are either supportive or investigational, and any use must be in the setting of clinical trials or specialist centers.
Optimized nutrition and micronutrient status
Good immunity in CTLN1 is mainly supported by adequate calories, balanced fats, vitamins, and minerals. Correcting deficiencies in vitamin D, zinc, and other micronutrients helps white blood cells work properly. This approach is simple but powerful and must be guided by regular lab checks and dietitian review.4Standard vaccinations and infection control
Maintaining up-to-date vaccines indirectly “boosts” immunity by preventing infections that could trigger catabolic states and hyperammonemia. This is not a drug in the classic sense, but a vital immune-support strategy in all urea-cycle disorders.3Gene-therapy research targeting ASS1
Experimental gene-therapy strategies aim to insert a healthy ASS1 gene into liver cells using viral vectors or genome-editing tools, restoring enzyme activity and normalizing ammonia handling.11 12 In preclinical models, these approaches show promise, but they remain under investigation and are not yet routine clinical care.11 12Hepatocyte (liver cell) transplantation (experimental)
Some centers have explored transplanting healthy liver cells into patients with urea-cycle disorders as a bridge to full liver transplant or as a partial correction. These cells may provide some functional ASS1 activity and lower ammonia, but long-term benefits and risks are still being studied.13Induced pluripotent stem cell (iPSC)–based models and therapies
Researchers have created iPSC models of CTLN1 to study disease mechanisms and test treatments in the lab.13 In the future, such cells might be engineered into hepatocyte-like cells for transplantation, but this is still at the research stage and not a current clinical option.13Future genome-editing strategies (CRISPR and others)
Animal and cell studies suggest that precise genome editing (such as CRISPR-based methods) could one day correct ASS1 mutations directly in the liver. At present, these techniques are experimental and must balance potential benefits against off-target effects and long-term safety concerns.11 12
Surgical and procedural treatments
Orthotopic liver transplantation
A full liver transplant replaces the patient’s liver with a donor liver that has normal ASS1 activity. This can normalize the urea cycle and protect against future hyperammonemia, though lifelong anti-rejection drugs are needed. Transplant is considered for patients with recurrent crises or brain injury despite optimal medical therapy.1Living-donor liver transplantation
In some countries, a relative donates part of their liver. The donated segment can provide enough ASS1 activity, and the donor liver regenerates. This option may shorten waiting time compared with deceased-donor transplant but carries surgical risks for both donor and recipient.1Hemodialysis or continuous renal replacement therapy access
During severe hyperammonemic crises, rapid hemodialysis or continuous renal replacement therapy is often needed to remove ammonia. To perform these treatments, surgeons or interventionalists place large venous catheters. These catheters are temporary but life-saving in acute decompensation.9Gastrostomy tube placement (G-tube)
A feeding tube placed directly into the stomach can help children who cannot reliably take enough formula by mouth. It allows precise delivery of medical formula, medicines, and emergency carbohydrate drinks, which improves nutritional status and reduces missed doses.4Central venous port or long-term line
Some patients with frequent hospitalizations or IV treatments receive an implanted port or tunneled central venous catheter. This makes repeated blood draws and infusions easier but carries risks of infection and clotting, so meticulous care is required.9
Prevention and long-term self-care
Keep to your prescribed low-protein diet and medical formula every day.3
Never fast for long periods; use frequent meals and bedtime snacks.3
Follow your sick-day plan early when you feel unwell; do not wait.9
Take nitrogen-scavenging drugs and supplements exactly as prescribed.5 8
Attend all follow-up appointments and monitoring blood tests.1
Stay up-to-date with vaccinations and infection-prevention measures.3
Avoid high-protein fad diets, bodybuilding supplements, and unregulated herbal products.3
Carry an emergency letter or ID card and know which hospital to attend.9
Educate school, employers, and close friends about warning signs and emergency steps.1
Seek emotional and social support to avoid burnout and treatment fatigue.1
When to see doctors or go to emergency care
People with CTLN1 should contact their metabolic team early for any fever, vomiting, poor intake, or new behavior changes, even if they seem mild. Early advice may include temporary protein restriction, extra carbohydrate drinks, or increased monitoring, which can prevent a serious crisis.3 9
Emergency services should be called or the person should be taken to hospital immediately if there is confusion, extreme sleepiness, odd behavior, slurred speech, unsteady walking, seizures, or loss of consciousness. These may be signs of dangerously high ammonia. In hospital, doctors can check ammonia levels, start IV glucose and ammonia-scavenging drugs, and arrange dialysis if needed.1 9
What to eat and what to avoid
Eat: measured amounts of low-protein breads, pasta, and cereals recommended by your dietitian, to provide energy with controlled protein.3
Eat: plenty of fruits and allowed vegetables for vitamins, minerals, and fiber, within the plan your team provides.4
Eat: prescribed medical formula exactly as instructed; it is your “metabolic medicine food.”4
Eat: healthy fats such as allowed plant oils or measured MCT oil for calories without protein.3
Eat: frequent snacks to prevent long fasting states, especially before bedtime or activity.3
Avoid: large portions of meat, poultry, fish, eggs, cheese, and other high-protein foods unless specifically measured by your dietitian.3
Avoid: high-protein “fitness” shakes, bars, and bodybuilding supplements that are not approved by your metabolic team.3
Avoid: skipping meals, fad weight-loss diets, or prolonged fasting, which can rapidly raise ammonia.3
Avoid: alcohol in adolescents and adults, as it stresses the liver and can worsen metabolic control.3
Avoid: herbal or “detox” products with unknown ingredients or hidden protein unless checked by your doctor.3
Frequently asked questions (FAQs)
Is citrullinemia type I curable?
Right now, CTLN1 is usually managed rather than cured. Diet, medicines, and careful monitoring keep ammonia under control. Liver transplantation can effectively correct the urea-cycle defect in many patients, but it is major surgery with lifelong anti-rejection treatment. Gene therapy and genome-editing approaches are under study for the future.1 11How is CTLN1 diagnosed?
Diagnosis is based on high blood citrulline, raised ammonia, specific amino-acid patterns, urine orotic acid, and genetic testing of the ASS1 gene. In many countries, newborn screening can detect CTLN1 before symptoms, allowing early treatment to protect the brain.1 2Can adults be newly diagnosed?
Yes. Some people with milder variants present later with headaches, confusion, psychiatric symptoms, or after stress such as infection or childbirth. Genetic testing and metabolic evaluation can confirm CTLN1, even in adults.1Why is ammonia so dangerous?
Ammonia is toxic to brain cells. High levels cause swelling of the brain, leading to irritability, vomiting, sleepiness, confusion, seizures, and coma. Fast recognition and treatment of hyperammonemia are critical to preventing permanent brain injury or death.1 13Will my child have normal growth and development?
Many children with early diagnosis and good control of ammonia grow and develop relatively well. However, those who have had severe neonatal crises may have developmental delays or learning problems. Close developmental follow-up and early therapies offer the best chance of good outcomes.1 4Is pregnancy possible for someone with CTLN1?
Pregnancy is possible but needs careful planning with a metabolic and high-risk obstetric team. Diet and medicines may need adjustment, and there is a risk of hyperammonemia during pregnancy and especially after delivery. Close monitoring and a clear birth plan are essential.1Can a baby with CTLN1 be breastfed?
In some cases, breastfeeding is possible but must be carefully measured and combined with medical formula to control total protein intake. The metabolic team will calculate safe amounts and monitoring schedules for the baby’s ammonia and amino acids.4Are vaccines safe for CTLN1 patients?
Yes, routine vaccines are recommended and important. They help prevent infections that could trigger catabolism and hyperammonemia. During fever after vaccination, parents should follow the sick-day plan if needed.3Can CTLN1 patients play sports?
Most patients can participate in moderate physical activity, which is healthy for the heart, bones, and mood. They should avoid long fasting before exercise and extreme over-exertion. The metabolic team and physiotherapist can help design safe activity plans.3Is school or regular work possible?
With good metabolic control and support, many individuals attend mainstream school and later hold jobs. Some may need individualized education plans or workplace accommodations to manage fatigue, clinic visits, and diet/medicine schedules.1What happens during a metabolic crisis in hospital?
In hospital, doctors check ammonia, start IV glucose, give IV nitrogen-scavenging medicines, stop protein temporarily, and may arrange dialysis to remove ammonia quickly. Patients are often treated in intensive care, with close monitoring of brain status and vital signs.9Can siblings or future children be tested?
Yes. Once the family’s ASS1 mutations are known, carrier testing and prenatal or pre-implantation genetic diagnosis are possible. Newborns in the family can be tested very early so treatment can start before symptoms.2 1Are there clinical trials for CTLN1?
Research is ongoing into gene therapy, improved nitrogen-scavenging regimens, and cell-based treatments. Families can discuss clinical-trial options with their metabolic center or patient organizations, which often list open studies.11 13Can regular doctors manage CTLN1 alone?
Because CTLN1 is complex and potentially life-threatening, care should be led or co-managed by an experienced metabolic specialist. Local pediatricians or internists can help with routine issues, but emergency protocols and long-term plans should come from a metabolic center.1Where can families find reliable information and support?
Reliable information comes from metabolic clinics, national rare-disease organizations, and peer-reviewed medical literature. Patient networks and charities for urea-cycle disorders provide education materials, family stories, and advocacy for research and access to care.1 10
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.
