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.

• Poor Feeding

  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]

  Clinical considerations: Poor feeding Vomiting Lethargy Hypotonia Tachypnea Seizures Measure ammonia if infant is symptomatic No dietary intervention is needed at this time. Continue to feed the baby if well. [archildrens.org]

  Citrullinemia or ASS deficiency in its classical form presents in the neonatal period with poor feeding, hyperammonemia, encephalopathy, seizures, and if untreated can be fatal. [ncbi.nlm.nih.gov]

• 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]

• Feeding Difficulties

  By 72 hours, lethargy, feeding difficulties and vomiting usually appear. The patient develops hypothermia, respiratory alkalosis and often requires ventilation. Seizures progressing to coma and death are typical in untreated patients. [rh.perkinelmer.com]

  A later onset presentation is less frequent and may be similar to or milder than the neonatal form and present with feeding difficulties, vomiting, episodic hyperammonemia, lethargy, seizures and cerebral atrophy on CT scans or MRI. [genedx.com]

  Infants appear normal at birth, but within the first week of life symptoms such as feeding difficulties, irritability, hypotonia, seizures, and vomiting present and eventually lead to premature death. [smpdb.ca]

  In severe forms, newborns present with hyperammonaemia, vomiting, feeding difficulties, and seizures soon after birth. [hindawi.com]

  difficulties, vomiting; 4 d: hepatopathy, hypoglycemia (26 mg/dl). [ncbi.nlm.nih.gov]

• Turkish

  Deutsch (German) العربية (Arabic) Français (French) Русский (Russian) ಕನ್ನಡ (Kannada) 한국어 (Korean) עברית (Hebrew) Український (Ukrainian) اردو (Urdu) Magyar (Hungarian) मानक हिन्दी (Hindi) Indonesia (Indonesian) Italiano (Italian) தமிழ் (Tamil) Türkçe (Turkish [definitions.net]

  For instance, the allelic frequencies of p.Gly390Arg in Indian and Turkish patients are 42.7 and 50%, respectively [22, 23]. [bmcmedgenet.biomedcentral.com]

• 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]

• Hypertension

  高血圧症/高血圧 hypertensive encephalopathy 高血圧性脳症 hypertensive nephrosclerosis 高血圧性腎硬化/高血圧性腎硬化症 hyperthermia 温熱療法/高体温/高熱/加温療法 hyperthyroidism 甲状腺機能亢進症 hypertransfusion 過剰輸血 hypertrichosis 多毛症 hypertriglyceridemia 高トリグリセリド血症 hypertrophic cardiomyopathy 肥大型心筋症 [jpeds.or.jp]

  Anakinra, an antagonist of the interleukin-1 beta receptor has proved to be efficient against the inflammatory signs, as well as against intracranial hypertension and hearing loss (if it is not too long-standing). [orpha.net]

  In patients subjected to bariatric surgery, the preoperative and actual weights, type of surgical technique, follow-up time, comorbidities (such as dyslipidemia, diabetes mellitus, arterial hypertension, obstructive sleep apnea, psychiatric disorders [scielo.isciii.es]

• Scotoma

  This later-onset form is associated with intense headaches, blind spots (scotomas), problems with balance and muscle coordination (ataxia), and lethargy. [medlineplus.gov]

  It is characterized by significant episodes of hyperammonemia, the neurologic symptoms may include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, somnolence, respiratory alkalosis and tachypnea. [flipper.diff.org]

• Abnormal Behavior

  He began to exhibit aberrant behavior accompanied by cloudiness of consciousness. Thereafter, he exhibited partial seizures followed by a twilight state or abnormal behavior. [ncbi.nlm.nih.gov]

  behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. [en.wikipedia.org]

• Aggressive Behavior

  0100738 Aggressive behavior Aggression Aggressive behaviour Aggressiveness [ more ] 0000718 Asterixis 0012164 Delirium 0031258 Delusions 0000746 Drowsiness Sleepy 0002329 Elevated hepatic transaminase High liver enzymes 0002910 Fluctuations in consciousness [rarediseases.info.nih.gov]

• Fidgeting

  They tend to fidget and run around much more than usual. Some children with hyperactivity need treatment. [newbornscreening.info]

• Lethargy

  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]

• Neurologic Manifestation

  Neurological manifestation in CTLN2 patients closely resemble those of hepatic encephalopathy and in the past, most patients usually followed rapidly deteriorating clinical courses and died of severe brain edema within a few years after onset. [webview.isho.jp]

  The incidence is estimated to be 1 per 57,000 of live births.[1] Infants are usually presented with severe attacks of hyperammonemia characterized by gastrointestinal and neurologic manifestations. [ncbi.nlm.nih.gov]

  Neurological manifestations of the Mendelian-inherited autoinflammatory syndromes. Dev Med Child Neurol 2009; 51: 420-428. Neven B, Prieur A-M, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. [dermnetnz.org]

  manifestations closely resembling those of hepatic encephalopathy. [jnnp.bmj.com]

  Classic CTLN1 often presents early in the neonatal period in affected individuals with acute hyperammonemia and neurologic manifestations. [frontiersin.org]

• Slurred Speech

  Another late onset form, common in Japan, has been reported in individuals as late as 20 years of age with milder presentation including slurred speech, irritability and insomnia as presenting signs. [genedx.com]

  Prior to transfer to our hospital, he had been living in a sanatorium in a bed ridden state with slurred speech and motor weakness. Subsequent brain computed tomography demonstrated progressive diffuse brain atropy. [docksci.com]

  Other symptoms of increased ammonia in the blood include: Headaches Vomiting Sleepiness Poor appetite Slurred speech Poor coordination Episodes of high ammonia can occur after going without food for a long time, like after an illness, or after a high-protein [rareguru.com]

  It is characterized by significant episodes of hyperammonemia, the neurologic symptoms may include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, somnolence, respiratory alkalosis and tachypnea. [flipper.diff.org]

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].

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.