Citrullinemia is a rare inherited disorder of the urea cycle, the metabolic pathway your body uses to convert ammonia into urea so it can be safely excreted. When the cycle stalls, ammonia builds up in the blood and can damage the brain and other organs. There are two distinct types, each caused by a different genetic defect and each following a surprisingly different clinical course, which makes the condition more varied and harder to recognize than many rare metabolic diseases.
Two Types, Two Different Genes
Citrullinemia type 1 (CTLN1) results from mutations in the ASS1 gene, which encodes the enzyme argininosuccinate synthetase. That enzyme catalyzes a key step in the urea cycle: converting citrulline and aspartate into argininosuccinate. When ASS1 doesn’t work properly, citrulline accumulates in the blood and ammonia rises to dangerous levels.1PubMed Central. Citrullinemia type 1 manifesting with a stroke-like episode: a case report Both copies of the gene must be faulty for the disease to appear, making it autosomal recessive. Parents are typically carriers with no symptoms of their own.
Citrullinemia type 2 (CTLN2) has a completely different genetic basis. It stems from mutations in the SLC25A13 gene, which encodes a mitochondrial protein called citrin. Citrin’s job is to shuttle aspartate out of the mitochondria and into the cell’s main compartment, where it feeds into the urea cycle. Without functional citrin, the urea cycle is starved of one of its ingredients, and ammonia again builds up, though by a different mechanism than in type 1.2Journal of Human Genetics. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD) Like CTLN1, citrin deficiency is autosomal recessive.
Citrin deficiency doesn’t always look the same at different life stages. In newborns it can cause a liver condition called neonatal intrahepatic cholestasis (NICCD). Some children go through a period of poor growth and abnormal blood lipids after the newborn stage. And a subset of adults with citrin deficiency develop full-blown CTLN2 with hyperammonemia and neurological symptoms.3PubMed Central. Clinical landscape of citrin deficiency: A global perspective on a multifaceted condition Not everyone who carries two faulty SLC25A13 alleles progresses to the adult-onset crisis; researchers believe additional genetic or environmental factors determine who does.4Journal of Human Genetics. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)
How Citrullinemia Shows Up
The classic presentation of CTLN1 is a newborn who seems fine at birth but rapidly deteriorates within the first few days of life as ammonia climbs. Symptoms of hyperammonemic encephalopathy in neonates include poor feeding, vomiting, lethargy, seizures, and coma. In a study of twenty Korean patients with CTLN1, fourteen had neonatal onset with hyperammonemic encephalopathy, and those babies often sustained extensive brain injury very early, progressing to brain atrophy at a young age.5PubMed. High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations That same study also identified three patients with late onset and three who were caught before symptoms appeared through screening or family history, showing that CTLN1 can present across a spectrum from catastrophic neonatal crisis to a milder form that surfaces later in childhood or even adulthood.
Late-onset CTLN1 can be deceptive. One case describes a ten-year-old boy who arrived at the hospital with rapidly worsening confusion and brain imaging that looked like herpes encephalitis. He improved with antiviral treatment and was sent home, only to return months later after starting a seizure medication that pushed him into hyperammonemic crisis, at which point citrullinemia was finally diagnosed.6PubMed Central. Late-Onset Citrullinemia Type I: A Radiological Mimic of Herpes Encephalitis Adult-onset CTLN1 is even rarer but has been documented, including in a postpartum woman who became obtunded four days after giving birth and required intubation before the diagnosis was made.7PubMed Central. Rare Adult-onset Citrullinemia Type 1 in the Postpartum Period: A Case Report
CTLN2 typically declares itself in adulthood, and often in a roundabout way. A 60-year-old man came to the hospital with finger tremors, confusion, and extremely high ammonia. Doctors initially suspected a blood vessel shunt in the liver was to blame, but treatment for that failed. Only after noting his unusual dietary preferences, including a strong craving for tofu and peanuts and an aversion to alcohol and sweets, did they suspect citrin deficiency. A blood test confirmed very high citrulline, and genetic testing confirmed CTLN2.8PubMed. Successful treatment of adult-onset type II citrullinemia with a low-carbohydrate diet and L-arginine after DNA analysis produced a definitive diagnosis Those dietary quirks are a telling clue: people with citrin deficiency often instinctively avoid carbohydrate-rich and sugar-laden foods, because carbohydrate metabolism places extra strain on the already broken metabolic pathway. They gravitate toward protein- and fat-rich foods instead.
Why Citrullinemia Gets Missed
Elevated citrulline in the blood is one of the markers measured in expanded newborn screening programs. A flagged result can point toward either CTLN1 or citrin deficiency, as well as a few other urea-cycle conditions.9PubMed. The diagnostic challenge of mild citrulline elevation at newborn screening The challenge is that citrulline levels in citrin deficiency can be only borderline elevated, so traditional screening thresholds sometimes miss affected babies. A Japanese program found that before adding a second-tier molecular test to newborn screening in 2018, twelve affected newborns were missed out of more than half a million screened. After the molecular follow-up was added, no cases were missed, and the detection rate roughly doubled.10PubMed. Improved diagnosis of citrin deficiency by newborn screening using a molecular second-tier test
Even outside the newborn period, diagnosis can be delayed. Adult-onset CTLN2 is easily confused with liver disease or psychiatric illness because confusion, personality changes, and abnormal liver tests are prominent features. CTLN1 presenting in older children or adults may be triggered by stress, illness, surgery, or medications that increase protein catabolism, and the initial workup often chases more common diagnoses first. A high ammonia level in someone who is confused should always prompt clinicians to check plasma amino acids, specifically looking for elevated citrulline, but that step is sometimes skipped when a more familiar diagnosis seems to fit.
Managing Acute Crises
When ammonia soars, the priority is getting it down fast. In neonates with CTLN1, continuous dialysis (called continuous venovenous hemofiltration, or CVVH) is more effective at clearing ammonia than peritoneal dialysis. In the Korean study mentioned earlier, six neonates treated with CVVH had more rapid ammonia reduction than seven treated with peritoneal dialysis, though most still suffered severe neurological damage because the brain injury often occurs before treatment can begin.11PubMed. High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations Continuous renal replacement therapy has also been used in adult crises, including in a pregnant woman with CTLN1 who developed hyperammonemia.12PubMed Central. Hyperammonemia in a pregnant woman with citrullinemia type I: a case report and literature review
Beyond dialysis, medications that provide alternative routes for nitrogen excretion are central to acute and chronic care. Sodium benzoate and sodium phenylbutyrate bind to amino acids and create compounds the kidneys can clear, effectively bypassing the broken urea cycle. Arginine supplementation is also standard because it provides the urea cycle with a substrate that helps pull some nitrogen through whatever residual cycle activity remains. During recovery from a crisis, protein intake is restricted while carbohydrate calories are kept high to minimize the body’s own protein breakdown, which would release more ammonia.13Clinical Nutrition Research. Nutritional Management in a Patient with Citrullinemia Type 1
Long-Term Dietary and Medical Treatment
Once stabilized, people with CTLN1 stay on a low-protein diet to limit the amount of nitrogen the urea cycle has to handle. The goal is to keep blood ammonia consistently below a safe threshold while still providing enough protein for growth and health. Oral nitrogen-scavenger drugs (sodium benzoate, phenylbutyrate) continue long-term, along with arginine supplements.14Clinical Nutrition Research. Nutritional Management in a Patient with Citrullinemia Type 1 Even with careful management, recurrent hyperammonemic episodes are a persistent threat. In the Korean cohort, about a third of patients experienced recurrent episodes, and a quarter had repeated bouts of acute liver dysfunction.15PubMed. High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations
Dietary management for CTLN2 looks very different from CTLN1, almost counterintuitive by comparison. Because citrin deficiency disrupts the way carbohydrates are metabolized in the liver, a low-carbohydrate, higher-fat and higher-protein diet is recommended. One case report described a patient whose symptoms improved on a low-carbohydrate diet combined with oral arginine after an initial misdiagnosis.16PubMed. Successful treatment of adult-onset type II citrullinemia with a low-carbohydrate diet and L-arginine after DNA analysis produced a definitive diagnosis This opposite dietary approach is one of the reasons distinguishing between type 1 and type 2 matters so much: prescribing a high-carbohydrate diet to someone with citrin deficiency, as would be standard for type 1, could make things worse.
Liver Transplantation
For severe CTLN1, especially the neonatal-onset form, liver transplantation is the only treatment that truly corrects the metabolic defect. The transplanted liver produces functional ASS1 enzyme, restoring the urea cycle. One series of seven pediatric transplants for neonatal-onset CTLN1 reported 100 percent patient survival over a median follow-up of about three years, with graft survival at 86 percent. After transplantation, none of the six children with intact grafts had any further metabolic crises, and they were able to eat a normal diet.17PubMed. Liver transplantation for neonatal-onset citrullinemia A separate report confirmed that transplantation normalized plasma ammonia and citrulline levels and eliminated the abnormal urinary markers that characterize the disease.18PubMed. Outcome of Liver Transplantation for Neonatal-onset Citrullinemia Type I
Liver transplantation is also considered the definitive treatment for CTLN2 when medical and dietary management fails, since citrin is expressed in the liver. The decision to transplant depends on the severity and frequency of crises, because transplant carries its own lifelong risks, including the need for immunosuppressive drugs and the possibility of graft complications.
Predicting How Severe the Disease Will Be
One of the hardest questions families face is whether a child’s citrullinemia will be mild or devastating. Research has identified residual enzyme activity as a useful predictor. In a study of patients with CTLN1, those whose ASS1 enzyme retained more than about 8 percent of normal activity had significantly fewer hyperammonemic episodes per year, lower peak ammonia during crises, and better cognitive function compared to those with less residual activity.19PubMed Central. Early prediction of phenotypic severity in Citrullinemia Type 1 That threshold isn’t a hard line, but it gives clinicians a rough guide to how aggressively to plan treatment early on.
Cognitive outcomes across urea cycle disorders generally track with how many hyperammonemic episodes a person has experienced and how high ammonia has climbed during the worst ones. Deficits tend to show up more in motor and performance tasks than in verbal skills.20PubMed Central. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium Early diagnosis and aggressive prevention of crises are the most reliable ways to protect the brain, which is part of why newborn screening programs are so consequential for these conditions.
Pregnancy as a Trigger
Pregnancy places unique metabolic demands on the body and is a recognized risk factor for unmasking or worsening citrullinemia, particularly CTLN1. The postpartum period seems especially dangerous, likely because the body shifts from the anabolic state of pregnancy (building tissue) to a catabolic state (breaking down tissue), which floods the urea cycle with nitrogen. As noted above, one case involved a previously healthy-appearing woman who became critically ill four days after delivery. Yet pregnancy in someone with known CTLN1 is not automatically catastrophic. A case report of a woman with untreated citrullinemia who carried a pregnancy to term with a normal outcome suggests that if metabolic crisis is avoided, successful pregnancies are possible.21PubMed. Pregnancy in a healthy woman with untreated citrullinemia Close monitoring of ammonia levels throughout pregnancy and especially in the postpartum period is essential.
Triggers and Medications to Watch For
Several situations can tip a person with citrullinemia from stable to crisis. Illness with fever, surgery, prolonged fasting, and high-protein meals are classic triggers for both types. Certain medications deserve special caution. Valproate, a common seizure drug, is notorious for raising ammonia levels and has precipitated life-threatening crises in undiagnosed patients with urea cycle defects. The case of the ten-year-old boy described earlier is a textbook example: he was stable until valproate was started, after which he rapidly decompensated.22PubMed Central. Late-Onset Citrullinemia Type I: A Radiological Mimic of Herpes Encephalitis Corticosteroids, which increase protein breakdown, and some chemotherapy agents can also raise risk. Alcohol appears to be another trigger: one adult-onset case involved a heavy drinker whose repeated episodes of confusion and high ammonia were triggered by excessive alcohol intake.23Internal Medicine. An Adult-onset Case of Argininosuccinate Synthetase Deficiency Presenting with Atypical Citrullinemia
For CTLN2 specifically, carbohydrate loading and intravenous glucose infusions, treatments commonly given to sick or fasting patients, can paradoxically worsen hyperammonemia. This is why accurately distinguishing type 1 from type 2 has real clinical consequences: the standard supportive care for metabolic crises (high-carbohydrate fluids) helps one type and harms the other.
Prevalence and the Geographic Dimension
CTLN1 is estimated to occur in roughly 1 in 57,000 to 1 in 250,000 births worldwide, depending on the population studied and the screening methods used. CTLN2 (citrin deficiency) is considerably more common in East Asian populations, particularly in Japan, China, and Korea. A nationwide Japanese study catalogued 345 patients with citrin deficiency, the great majority presenting as NICCD in the newborn period. The most common SLC25A13 mutation, a four-base-pair deletion, was found on about 42 percent of alleles in the NICCD group and 49 percent of alleles in adults with CTLN2.24PubMed Central. Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature Review A rapid genetic screening panel targeting eleven prevalent SLC25A13 mutations has been developed to simplify diagnosis in populations where these variants are common.25PubMed. Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13
Outside East Asia, citrin deficiency is much less recognized and probably underdiagnosed. Cases have been reported in Middle Eastern, European, and North American populations, but the variant spectrum is different and clinicians may not think of it. Any adult with unexplained hyperammonemia and an unusual dietary history, especially avoidance of carbohydrates and sweets, should prompt consideration of CTLN2 regardless of ethnic background.
Liver Complications Beyond Ammonia
The liver takes a beating in both forms of citrullinemia, and the damage isn’t limited to the metabolic crises themselves. Across urea cycle disorders, the liver can develop excessive glycogen storage, fatty-liver-like changes, and even acute liver failure. In citrin deficiency specifically, low blood sugar and progression toward cirrhosis have been described. Perhaps most sobering, liver cancer (hepatocellular carcinoma) appears to be disproportionately common in citrin deficiency and can sometimes occur even in patients without cirrhosis, which makes it harder to predict and screen for.26Springer Link / J Inherit Metab Dis. Liver involvement in urea cycle disorders: a review of the literature Long-term liver surveillance is part of the standard care plan for people living with either type of citrullinemia.
The Burden on Families
Managing a child with a urea cycle disorder is consuming. Frequent blood draws, emergency-room visits for intercurrent illness, strict dietary requirements, multiple daily medications, and the constant vigilance against ammonia spikes all take a toll on caregivers. A Japanese study of pediatric patients with inborn errors of metabolism found that health-related quality of life was substantially lower in children who also had developmental disabilities. Caregiver burden, measured by a validated questionnaire, correlated strongly with the child’s quality-of-life scores: the worse the child’s health-related quality of life, the greater the caregiver strain.27Springer Link / Quality of Life Research. Health-related quality of life and caregiver burden of pediatric patients with inborn errors of metabolism in Japan using EQ-5D-Y, PedsQL, and J-ZBI Access to metabolic-disease centers, genetic counseling, nutritional support, and respite care varies widely by region and can make a real difference in how families cope.
Gene Therapy on the Horizon
Because citrullinemia is caused by a single-gene defect expressed primarily in the liver, it is a natural candidate for gene therapy. Researchers have been testing approaches in mouse models of lethal CTLN1. One group used an AAV8 viral vector to deliver a CRISPR-based system that permanently inserted a working copy of the ASS1 gene into liver cells. Treating newborn mice completely rescued what would have been a fatal disease, with survival extended to at least five months and a significant drop in circulating citrulline. Interestingly, the best strategy depended on when treatment was given: in newborn mice, the integrating (permanent) approach worked better, while in older juvenile mice, a non-integrating vector that simply expressed the gene without inserting it into the genome produced better results, normalizing both ammonia and citrulline to healthy levels.28Molecular Therapy Methods & Clinical Development. Development of viral and non-viral gene therapy approaches for repairing or expressing argininosuccinate synthase
These results are still preclinical, and translating mouse outcomes to human therapy involves substantial hurdles, including immune responses to viral vectors, the durability of gene expression as the liver grows and regenerates, and the challenge of dosing accurately in a newborn. But the mouse data is encouraging enough that clinical trials for urea cycle gene therapies are being actively planned. If successful, gene therapy could eventually offer an alternative to lifelong dietary restriction and medication, or to liver transplantation, for at least some patients with citrullinemia.