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]:

• Anorexia and vomiting
• Irritability and combativeness
• Tachypnea and labored breathing
• Lethargy
• Disorientation
• Asterixis (rare)
• Seizures
• Coma
• Cerebral edema
• Death (if treatment is not forthcoming or effective)

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.

• Developmental Delay

  The end result is hyperammonemia which can cause life-threatening neurologic symptoms and global developmental delay. [ncbi.nlm.nih.gov]

  He has short stature, webbing of his hands, pulmonary stenosis, seizures and hydrocephalus along with developmental delay. [ggc.org]

  Analyzes chromosomes in newborns and infants for changes that can explain certain birth defects or developmental delays. Multiple testing options providing information on the genetic health of your baby during the first and second trimesters. [integratedgenetics.com]

  Individuals with classical citrullinemia type 1 often present early in the neonatal period with metabolic coma due to hyperammonaemia, which if untreated proves fatal, but with treatment leads, instead, to developmental delay of varying degrees of severity [testguide.adhb.govt.nz]

• Asymptomatic

  Many newborn screening programs have recently been expanded to include citrullinemia and numerous asymptomatic hypercitrullinemic infants and children have been identified. [ncbi.nlm.nih.gov]

  Mild or asymptomatic forms of the disease, in which there is elevated serum citrulline, but no hyperammonaemia, have also been described. [testguide.adhb.govt.nz]

• Fatigue

  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 [medlineplus.gov]

  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]

  […] with purpura, convulsive seizures and methioninemia]. 61 24 Wen PQ...Li CR 24327139 2013 42 [A case of neonatal intrahepatic cholestasis caused by citrin deficiency complicated with congenital biliary atresia]. 61 24 Tong F...Yang RL 24484564 2013 43 Fatigue [malacards.org]

• Malaise

  •Schnitzler Syndrome •Blau (NOD2) (PGA) •NLRP12 •CANDLE syndrome •Behcets •SJIA Downloads References Links Clinical Trials Connect Support News NOMID/CINCA Common Symptoms Present in All CAPS Disorders: • Rash • Headaches • Periodic Fevers • General Malaise [autoinflammatory.org]

• Cough

  COVID-19 symptoms means fever of 100.4 degrees Fahrenheit or higher, chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting [lawinsider.com]

• Mild Clinical Course

  The infantile form presents after the age of 5 months and usually has a mild clinical course. [ajnr.org]

• Vomiting

  Affected infants typically appear normal at birth, but as ammonia builds up in the body, they develop a lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. [en.wikipedia.org]

  Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat, and ankle clonus. [rarediseases.org]

• Nausea

  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]

• Irritability

  From Wikipedia, the free encyclopedia Citrullinemia Other names Citrullinuria L-Citrulline Specialty Medical genetics Symptoms Extreme sleepiness, no appetite, irritability, vomiting, muscle weakness, breathing problems. [en.wikipedia.org]

  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]

• Headache

  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]

  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]

  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]

• Forgetful

  […] triglycerides Increased serum triglycerides Increased triglycerides [ more ] 0002155 Hypoalbuminemia Low blood albumin 0003073 Hypoproteinemia Decreased protein levels in blood 0003075 Irritability Irritable 0000737 Lethargy 0001254 Memory impairment Forgetfulness [rarediseases.info.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].

• Hyperammonemia

  Citrullinemia type 2 is common in East Asians and usually presents in adults with hyperammonemia and neuropsychiatric disease. It may also cause neonatal or infantile cholestatic liver disease without hyperammonemia, which is usually transient. [medlink.com]

  Treatment The symptoms of citrullinemia seem to originate from the hyperammonemia rather than citrulline accumulation. [rh.perkinelmer.com]

  Treatment of acute hyperammonemia in an infant is given in the Table 1. Specific medication for hyperammonemia includes sodium benzoate and phenyl acetate [ 5 ]. [omicsonline.org]

  Some individuals with CTLN1 do not experience symptoms or hyperammonemia. [rarediseases.org]

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].

Mortality/Morbidity

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

Sex

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

Age

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.

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].

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.