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Citrullinemia Type 1

Citrullinemia is an autosomal recessive inherited disorder caused by arginosuccinate synthetase deficiency, an enzyme involved in the urea cycle.


Prenatal diagnosis is possible but is available only at research centers. DNA testing is possible, using amniotic or chorionic villi sampling. No routine laboratory studies help in the diagnosis. Only when a metabolic disorder is suspected, due to the occurrence of symptoms, may the physician obtain serum ammonia levels that are diagnostic.

Symptoms of hyperammonemia include some or all of the following [6]:

Children with citrullinemia demonstrate delayed development from infancy, including cognitive, gross-motor, and fine-motor impairments . The presence of these delays may be the only reason for the physician to suspect the disorder [6].

Complications are chiefly neurologic, including mental retardation, encephalopathy, coma, and death.

  • Symptoms of a metabolic crisis include: poor feeding vomiting extreme fatigue excessive sleepiness irritability muscle spasms If a metabolic crisis is not treated, breathing problems, seizures, coma, brain damage and sometimes death can occur.[newbornscreening.on.ca]
  • Symptoms of this form include headaches, visual disturbances, problems with balance and coordination and fatigue. How common is citrullinemia? Type I neonatal citrullinemia is rare, approximately 1 in 57,000 infants worldwide.[symptoma.com]
  • In rare cases, affected individuals develop other signs and symptoms in early childhood after seeming to recover from NICCD, including delayed growth, extreme tiredness (fatigue), specific food preferences (mentioned above), and abnormal amounts of fats[ghr.nlm.nih.gov]
  • […] with purpura, convulsive seizures and methioninemia]. 38 4 Wen PQ...Li CR 24327139 2013 42 [A case of neonatal intrahepatic cholestasis caused by citrin deficiency complicated with congenital biliary atresia]. 38 4 Tong F...Yang RL 24484564 2013 43 Fatigue[malacards.org]
  • If this does not happen the individual, before to develop the characteristic features of adult-onset type II citrullinemia, experiences a state of apparent health characterized by fatigue, growth retardation, hypoglycemia, and pancreatitis.[flipper.diff.org]
Down Syndrome
  • We summarize the diagnosis, outcome, and molecular studies of five Mediterranean patients with citrullinemia: four neonatal classical forms and one subacute form, who also suffers from Down syndrome and presented with severe hepatic encephalopathy at[ncbi.nlm.nih.gov]
  • The clinical features include vomiting, convulsions, and coma.[medical-dictionary.thefreedictionary.com]
  • Poor feeding and lethargy progress to vomiting, irritability, impaired consciousness, tachypnea, seizures, and apnea. Intracranial pressure is usually increased because of cerebral edema.[accessanesthesiology.mhmedical.com]
  • All three had episodes of vomiting, lethargy and hyperammonemia shortly after birth. The two more severe cases developed convulsions. They were saved by peritoneal dialysis, or repeated exchange transfusions followed by dietary adjustment.[ncbi.nlm.nih.gov]
  • Infants are normal at birth followed by an acute illness characterized by hyperammonemia, anorexia, vomiting, lethargy, and hepatomegaly in some cases, increased intracranial pressure, seizures and coma.[genedx.com]
  • Watch for signs of ammonia build-up (also called hyperammonemia) including: nausea, vomiting, sleepiness, or unusual problems with your mood or thinking. If you have any of these, get medical care right away.[newenglandconsortium.org]
  • Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat, and ankle clonus.[rarediseases.org]
  • This did not agree with our initial diagnosis of nonketotic hyperglycinemia where hiccups is present more often.[ncbi.nlm.nih.gov]
Skin Lesion
  • Since the patient's skin lesions responded to arginine supplements, and since arginine is a component of keratin, we postulate that the skin lesions are the result of arginine deficiency.[ncbi.nlm.nih.gov]
Blonde Hair
  • The hair changes mentioned by other authors in newborns and young children, i.e. sparse and brittle blond hair, presence of transverse opaque bands ('irregularly banded hair'), were not present in our case.[ncbi.nlm.nih.gov]
  • Physical examination at the time of admission revealed a responsive but somewhat irritable child who fell in the tenth percentile for both height and weight. The spleen and liver were not palpable. The child[jamanetwork.com]
  • Characteristic features include confusion, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma.[treatable-id.org]
  • There's also a form that occurs during or after pregnancy, and a form with no symptoms. [1] [2] In the classic form, symptoms occur right after birth and include excessive sleepiness, poor appetite, vomiting, and irritability.[rarediseases.info.nih.gov]
  • A less common and milder form of the disease will cause clinical symptoms to present later in life and typically take the form of headaches, ataxia (issues with balance and muscle coordination), partial loss of vision, and lethargy.[nxgenmdx.com]
  • Onset may also occur in adults, where the disease is characterized by periods of hyperammonemia, reduced alertness, headache or migraine. Patients with adult-onset disease may present with liver failure instead of neurological symptoms.[sema4.com]
  • Common Features of the Disorder Vomiting Difficulty feeding Lethargy Seizures Intellectual disability Headaches Vision loss Prognosis Features of the disorder typically develop in the first week of life.[evolvegene.com]
  • These symptoms can include, but are not limited to, mood changes, disorientation, headaches, low energy, vomiting, and refusal to eat. Mode of inheritance Citrullinemia type 1 is inherited in an autosomal recessive pattern.[my46.org]
Profound Mental Retardation
  • Despite treatment, morbidity and mortality of this disease remain high, and long-term complications include mild to profound mental retardation, seizures, and growth deficiency.[ncbi.nlm.nih.gov]


In patients with symptoms of citrullinemia, the measurement of blood ammonia levels is the primary laboratory test in diagnosis. No other routine studies provide useful information for diagnosis.

Magnetic resonance imaging (MRI) of the brain in affected infants, may show abnormalities which are not diagnostic , but may be helpful in predicting the extent of neurological complications [2].

EEG Normal
  • Finally, the manner in which the EEG normalizes during recovery from hyperammonemia in this setting suggests that burst-suppression resembles an exaggerated regression to the discontinuity of the very premature infant.[ncbi.nlm.nih.gov]
Multifocal Spikes
  • Multifocal spikes or repetitive paroxysmal activity of various kinds were seen in the EEGs at times of crisis. There was a lag in the EEG returning to normal after ammonia levels had returned to normal. Citrulline remained elevated in all cases.[ncbi.nlm.nih.gov]


The treatment of hyperammonemia is the primary intervention in citrullinemia. Intravenous sodium benzoate, sodium phenylacetate, and arginine are used to reduce blood ammonia levels. Intravenous benzoate and phenylacetate are still considered experimental drugs. They provide alternate pathways for nitrogen waste disposal. Benzoate forms hippuric acid, which is rapidly excreted by the kidney. Phenylacetate combines with glutamine to form phenylacetylglutamine, and is also more easily excreted in this form.

In severe cases, hemodialysis may be needed to rapidly reduce the blood ammonia level. Long-term management of citrullinemia requires strict dietary changes, low-protein and pyruvate diets, as well as oral administration of sodium phenylbutyrate and arginine. Referral to a nutritionist for monitoring and education in the low-protein diet is necessary. Frequent monitoring of blood amino acid levels is also important in order to insure that essential amino acid levels remain normal.

Liver transplantation is a very promising therapy. The procedure has been used in several cases with excellent results [6].

Gene-transfer may be a cure in the future. A partial correction of the enzyme defect has been seen in trials [3].


In the past, most patients were treated with medication and died of severe brain edema within a few years of onset. Currently, with appropriate treatment, survival is possible into adulthood. During the last decade a small number of patients have undergone liver transplantation with good results [1].

Patients who received living, partial liver transplantation had remission of the neurological symptoms [1]. In patients without liver transplantation, approximately half died of encephalopathy or hepatic cancer [1]. The other half of non-transplant patients had good clinical outcomes with treatment with medication (oral L-arginine) and low- protein diets [1].

The outcome of neonatal citrullinemia continues to be poor. Ammonia levels at diagnosis is the only indicator of prognosis [2]. The higher the levels the more dire the prognosis.
The degree of cognitive delay in patients with citrullinemia is roughly equal to how severe the initial symptoms and the frequency of episodes of elevated ammonia levels [5].

Both parents of an affected infant are heterozygotes carriers of the trait because citrullinemia is an autosomal recessive disease. The probability of a subsequent child having the disease born of these parents is 1 in 4, or 25%. Genetic counseling is necessary for any family with a member with the disease.


Citrullinemia is an autosomal recessive genetic mutation of Chromosome 9. The two forms of the disease are actually two separate disorders because the mutations occur in different places on the chromosome [3].

Occurrence of the neonatal disorder depends on both parents having the defective gene and the probability of it being passed on to their children is 1 in 4.

Untreated neonatal citrullinemia is almost always fatal. However, morbidity from Citrullinemia type II is dictated by other genetic and environmental factors [1].


The incidence of citrullinemia is not known because it is such a rare disorder and also because screening is not currently routinely done. Mass screening for the adult-onset citrullinemia gene is done only in East Asia [4].


Morbidity and mortality rates are high, but again are unknown because of the lack of data.


Citrullinemia is inherited as an autosomal recessive trait, thus, both genders are equally affected.


The age of presentation can vary widely, although the most common presentation is in the neonatal period. Older children not treated in the neonatal period may be diagnosed later as part of an evaluation for the etiology of their mental retardation.

Sex distribution
Age distribution


The urea cycle is responsible for the disposal of waste nitrogen from the body. Protein and amino acid metabolism result in the production of waste nitrogen. The genetic mutation found in citrullinemia blocks urea production and results in hyperammonemia. N -acetylglutamate, an enzyme activator , incorporates ammonia into the cycle [1].

This enzyme facilitates the combination of aspartic acid and citrulline to form argininosuccinic acid [1]. The urea-cycle, therefore, promotes ammonia excretion. Disruption of the urea cycle results in the accumulation of ammonia in the body [2].

Mortality and morbidity from the disease are directly related to the concentration of ammonia in the body. The effect of hyperammonemia on the brain is the primary causes of injury, more so than cerebral edema [2]. Elevated cerebral ammonia level is the cause of the cerebral edema. It also results in the accumulation of lactate, and the alteration in neurotransmission and nitric oxide synthesis [2].

Glucocorticoids, glucagon and insulin control the functioning of this mutant gene, both during fetal development and in later life [5]. Protein and carbohydrate intake stimulates the activation of this argininosuccinic acid gene [3].


There are no guidelines for prevention of citrullinemia.


Citirullemia is a condition that results from a dysfunction of the urea cycle. The malfunction is a result of a mutation on chromosome 9 [1].

There are two forms of the disorder. Type I, neonatal Citirullemia, is an autosomal recessive defect which requires the inheritance of one gene mutation from each parent. Type II is the adult form of the disease and is due to a mutation on a different portion of chromosome 9. Type II Citirullemia occurs almost exclusively in Japan and the Far East [3].

The urea cycle is involved in the transformation of nitrogen and ammonia, the waste products of metabolism, into forms which can be excreted by the body. An interruption in the urea cycle results in the accumulation of ammonia and citrine in the body, causing cellular damage to multiple organs, but in particular the brain [1].

In neonates and infants this accumulation of ammonia causes the primary symptoms of the dieses: lethargy, cognitive and developmental delays, seizures, coma, and, eventual death [1].

Patient Information

What is citrullinemia?

Citrullinemia is an inherited, metabolic disorder. It is caused by a genetic mutation on Chromosome 9 witch results in the malfunction of the urea cycle. The urea cycle is responsible for the conversion of nitrogen, a waste product of metabolism, into forms that can be easily excreted from the body. High levels of ammonia build up in the bloodstream.

The nervous system is particularly susceptible to the toxic effects of ammonia, causing swelling of the brain and interference with the transmission of electrical impulses throughout the nervous system.

There are two forms of citrullinemia. Neonatal citrullinemia, type I, is present at birth. Infants with this disorder are usually diagnosed in the new-born nursery. As ammonia builds up in the body they begin to have symptoms. They tend to be lethargic and feed poorly. Gradually the symptoms become more severe progressing to vomiting, seizures, and coma. If untreated the disorder is life-threatening and death ensues.

Type II citrullinemia can occur in later childhood or adulthood. Symptoms of this form include headaches, visual disturbances, problems with balance and coordination and fatigue.

How common is citrullinemia?

Type I neonatal citrullinemia is rare, approximately 1 in 57,000 infants worldwide. Type II citrullinemia occurs almost exclusively in the Japan. Its incidence is estimated to be 1 in 230,000 Japanese. Type II also has been reported rarely in the Middle East.

How do people inherit citrullinemia?

Citrullinemia is inherited from both parents have the mutated gene trait, as it is an autosomal recessive genetic disease.

Generally neither of the parents has the disease. The probability of two parents with the trait having a child with the disease is 1 in 4 or 25%. The probability of a family with one child with citrullinemia having another child with the disease is also 25%.

Genetic counseling is necessary for all families with a member who has been diagnosed with citrullinemia.

How is citrullinemia treated?

Citrullinemia is treated primarily with medications that reduce the ammonia levels by helping the body form other compounds with the excess nitrogen that are then excreted from the body.

Along with these medications, adherence to a low protein diet is essential. The supply of essential amino acids is compromised by this type of diet so the help of a nutritionist should be sought.



  1. Yazaki M, Ikeda S, Kobayashi K, Saheki T. Therapeutic approaches for patients with adult-onset type II citrullinemia (CITIRULLEMIA TYPE II): effectiveness of treatment with low-carbohydrate diet and sodium pyruvate. Rinsho Shinkeigaku. Nov 2010;50(11):844-7.
  2. Gunz AC, Choong K, Potter M, Miller E. Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. Int Med Case Rep J. Aug 19 2013;6:41-8.
  3. Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle. European Journal of Biochemistry, 2003, 270: 1887–1899.
  4. Eriguchi Y, Yamasue H, Doi N, Nishida T, Abe O, Yamada H, Aoki S, Suga M, Inoue H, Nonaka H, Obata T, Ikehira H, Kobayashi K, Kasai K. A case of adult-onset type II citrullinemia with comorbid epilepsy even after liver transplantation. Epilepsia, 2010, 51: 2484–2487.
  5. Kobayashi H, Saheki. Pancreatic secretory trypsin inhibitor as a diagnostic marker for adult-onset type II Citrullinemia. Hepatology Vol. 25, No. 5, 1997
  6. Kimura N, Kubo N, Narumi S, et al. Liver Transplantation Versus Conservative Treatment for Adult-Onset Type II Citrullinemia: Our Experience and a Review of the Literature. Transplant Proc. Nov 2013;45(9):3432-7.

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Last updated: 2019-07-11 22:09