Citrullinemia

This gene foresee instructions for making a protein called citrin. Type II also has been reported in other populations, including folks from East Asia and the Middle East. Researchers have found many infants with newborn intrahepatic cholestasis have the same mutations in the SLC25A13 gene as adults with type II citrullinemia. Type II citrullinemia is primarily found in the Japanese population, where it occurs in an estimated one in 100,000 to 230,000 individuals. Mutations in the SLC25A13 gene typically hinder cells from from any functional vitamin p, which inhibits the carbamide calendar and disrupted the production of proteins and nucleotides.

Type II has also been detail in people from East Asian and Middle Eastern populations.

These molecules are essential for the carbamide cycle and are also involved in making proteins and nucleotides. Type II citrullinemia may also develop in lede who had a liver disturbance called neonatal cholestasis during cradlehood. In many cases, the symptoms resolve within a year. Molecules transported by citrin are also involved in making nucleotides, which are the building blocks of DNA and its alchemical cousiness, RNA. This gene makes a protein called citrin, which normally reciprocate certain molecules in and out of mitochondria. The mother of an individual with an autosomal recessive condition each capture one copy of the mutated gene, but they typically do not show symbol and symptoms of the arrangement. Type I citrullinemia is the most national beauty of the malady, touching concerning 1 in 57,000 people worldwide. Within cells, citrin support transport molecules habit in the production and breakdown of simple sugar-coat, the fruit of proteins, and the urea motorcycle. Users seeking information about a personal genetic complaint, concurrence, or condition should consult with a limited healthcare professional. See How can I find a genetics professional in my scope? in the Handbook.

Mutations in the SLC25A13 gene are responsible for type II citrullinemia. Affected infants typically appearance normal at birth, but as ammonia builds up in the body, they lay open a lack of action (sleep), poor feeding, vomiting, seizures, and waste of consciousness. These iatrical problems can be life-lowering in many inclose. A milder form of typify I citrullinemia is less common in childhood or adulthood. Some people with gene mutations that motive represent I citrullinemia never experience signs and symptoms of the irregularity. The resulting buildup of ammonia and other toxic substances leads to the symptoms of type II citrullinemia. The resulting buildup of ammonia and other venomous substances direction to the signs and symptoms of adult-onset type II citrullinemia. This requisite blocks the passage of bile and deter the consistency from processing certain nutrients properly. A lack of bioflavinoid also precede to the features of NICCD, although ammonia does not construct up in the bloodstream of infants with this arrangement. Years or even decades later, however, some of these people develop the characteristic shape of adult type II citrullinemia.



Mutations in SLC25A13 typically debar the production of any official citrin, which prohibit the urea cycle and disrupts the fruit of proteins and nucleotides. Type II citrullinemia is found primarily in the Japanese population, where it happen in an estimated 1 in 100,000 to 230,000 individuals. The resources on this place should not be used as a apology for professional medical care or intelligence.

This plight is transmitted in an autosomal retrogressive pattern, which means both copies of the gene in each cell have mutations. Mutations in the SLC25A13 gene are responsible for grow-attack example II citrullinemia and NICCD. Type I citrullinemia (Online 'Mendelian Inheritance in Man' (OMIM) 215700, also understood as classic citrullinemia) usually becomes evident in the first few days of energy.

Reference

Citrullinemia. (2013). Retrieved on September 19, 2013, from http://en.wikipedia.org/wiki/Citrullinemia.

Citrullinemia. (2013). Retrieved on September 19, 2013, from http://ghr.nlm.nih.gov/condition/citrullinemia.

NTU successful treatment of rare diseases citrullinemia Thai boy

Thais in order to treat a rare disease citrullinemia suffering newborns , National Taiwan University Hospital ambulance recently went straight back out Taoyuan airport apron baby boy, and disdain for technology in Asian countries , as young as one month 's illness Tong hemodialysis three times ( dialysis ) , so that the original gravely ill little boy miraculously survived .

Department of Medical Genetics at NTU Hu says , citrullinemia first type is a urea cycle disorder , because children with genetic , congenital deficiency of an enzyme in vivo , resulting in a toxic protein foods citrulline can not accumulate in the blood is broken down , and the long-term accumulation of ammonia .

It was pointed out that the name of the baby's mother is immune Thai physicians , had confirmed that diseased child was born three days , but not for local children weighing less than twenty kilograms of hemodialysis , so the baby can only accept the less efficient the peritoneum dialysis treatment , the results are still soared along with high blood ammonia values ​​.

The network search , baby mother found the National Taiwan University Hospital in Taiwan , in Taiwan and Thailand two governments with the assistance of the morning made ​​contact with NTU , the next morning he took his parents to baby boy fly arrived in Taiwan , then from No. ambulance ride to sit straight apron NTU pediatric ICU.

Baby boy attending Jane Ying Xiu , said the baby to the hospital when the ammonia values ​​up to seventy to ○ ○ μmol / L ( normal or less than five ○ μmol / L), symptoms include drowsiness, liver and kidney failure and brain hemorrhage , the situation is quite critical.

She said the boy only four kilograms of fine blood vessels can imagine , but once NTU medical team records for only three kilograms of Bebi hemodialysis, accept this challenge is not a problem , and finally also proven to help the hospital before and after the baby conducted three of four hours dialysis , the process is very smooth .

Dr. Hu Director said , because the station would have to pay health care, even if the baby parents in Thailand are considered high-paying white-collar workers locally , still can not help but worry for the associated costs , for NTU especially parents contacted the McDonald's offers free accommodation, this multinational medical case gift warm.

After three weeks of treatment and follow , the original lie incubator , the Thai boy wearing a respirator , before finally able to safely return to the mother 's arms Thailand.

Citrullinemia

Citrullinemia urea cycle metabolism is one of these diseases is due to enzyme deficiency
Cause . Urea cycle, citrulline (citrulline) is Carbamoyl phosphate and
Ornithine ( ornithine ) after effects of the product. Under normal circumstances, citrulline further by spermine
Succinic acid synthase (argininosuccinate synthetase) and aspartic acid (asparate)
Combine to produce succinic acid spermine (argininosucinate, AS). Urea per molecule , including the
Two atoms of nitrogen (N), one from ammonia (NH3), one comes from aspartate
(asparate). argininosuccinate synthetase deficiency leads to the accumulation of citrulline , called
Citrullinemia first type .
        Most nitrogen from protein and amino acid metabolism, and the body to remove nitrogen urea cycle is the main road
Trail. Urea cycle in the liver in the performance , some of the reaction in the mitochondria , has a portion that is the fine
Cytoplasm inside, able to toxic substances ( ammonia ) , converted into a more toxic substances ( urea ) , followed by small
Then discharged . Mitochondrial metabolic disorder that may affect the urea generation , resulting in hyperammonemia . Overall speaking,
Urea cycle is subject to N- acetyl glutamate (N-acetylglutamate, NAG) synthesis rate adjustment
Control , this enzyme catalyst (NAG) turn ammonia into urea cycle .
         Argininosuccinate synthetase generally will be transported to the brain , kidney , skin and fibrous tissue
Mother cell effect, so citrulline outside can be metabolized in the liver . Citrullinemia patients with genetic defects
Among these organizations are manifested in . Urea cycle, citrulline and aspartate binding, the second
Waste nitrogen molecules into circulation ; damaged when the urea cycle , resulting in a reduced ability to excrete ammonia, 50% of patients
There hyperammonemia situation.

Genetic model
        Japan had cases in adults found a specific , previously undetected and treatment citrulline blood
Disease , there are patients in the 48 years after the discovery . Some patients have developmental delays during childhood years in question, but
Is that most of the patients before the onset of symptoms to the disease . So citrullinemia age of onset and birds
Formyl amino acid transfer enzyme deficiency (Orinithine transcarbamylase deficiency) a
Sample is unpredictable . Mortality and morbidity ratios are high .
        Citrullinemia is an autosomal recessive genetic disease , both parents are carriers of the recessive
(Carrier: parents, each with a defective gene , but no clinical symptoms ) , the patient must be
With two defective genes ( each get one by the parents ) until disease. As long as both parents are carriers, there is
25% chance of giving birth to sick children , there is a 50% chance for the child carriers . No gender diseased probability
Points.
        Citrullinemia causative gene is located in the ninth chromosome (9q34). At least 20 sudden
Point was found. Age of onset urea cycle with other metabolic disorders same variable age of onset ,
The most common age of onset neonatal period . Neonatal period and grew up in Children with no treatment , there may be wisdom
Force barrier consequences.
Symptom
       
        Symptoms of high blood ammonia , along with lack of appetite , vomiting , fatigue, irritability , cramps ; cerebral edema and faint
Fans , if untreated may lead to death. Typically onset neonatal period , but symptoms may be a few days
After a few weeks before or after being noticed . Clinical symptoms and severity vary depending on individual circumstances . Generally
May appear hyperammonemia status, growth is poor. If the brain edema may cause papilledema
(Papilledema), intracranial pressure will increase. Lungs , it may have shortness of breath or too strong
Circumstances may apnea or late failure. Moderate hepatomegaly may also occur a phenomenon . Neurological side
Surface , there may be poor coordination , rotation movement disorder (dysdiadochokinesia), the tension is too low or
Too strong , ataxia , tremors , convulsions , drowsiness . The main complications of neuropathy, including intellectual impairment
Obstruction , acute hyperammonemia coma , or even death.
Diagnosis
         For symptomatic patients , the primary measurement of the blood that is ammonia (NH3) concentration was useful for diagnosis
Biochemical values. Again is a measure of the concentration of amino acids in the blood , the incidence of patients whose serum citrulline significantly
Rise to 1000-5000  M ( normal 10-20  M). Amino acid concentration in the urine of patients ,
Concentrations of organic acids and urine orotic acid (orotic acid) can also be used as reference values. Orotic acid in the urine of patients
Concentration will rise.
        Measurement of skin fibroblasts of Argininosuccinate synthetase, can provide clear
Biochemical diagnosis.
Prenatal diagnosis
May have an amniocentesis (amniocytes) or chorionic villus do molecular diagnostics .
Treatment
        The goal of treatment is to fix biochemical imbalance and to ensure nutritional needs. Situation in hyperammonemia
Under the immediate restricted diet of protein, non-protein source of heat strengthened to avoid decompensation . Serious
It may quickly remove ammonia in hemodialysis .

Low-protein diet
        According to the patient 's age and the severity of the disease protein intake determine each patient 's needs
Requirements are quite different . Six months ago, because it is a period of rapid growth , the patient may need
1.5g/kg/day or more protein ; preschool period , protein intake is usually reduced to
1.2 ~ 1.5g / kg / day; school-age children , you can be reduced to 1 g / kg / day. After puberty , the protein
Amount can be less than 0.5g/kg/day.
Drug
Drugs provide an alternative way to eliminate waste nitrogen .
1.Sodium benzoate (Ucephan): with glycine (glycine) combine to form hippuric acid
(Hippurate), and then by the urine. Every 1 mole of benzoate remove one mole of nitrogen. Generally
The IV dose to 250 mg / kg / day; oral doses of 375mg/kg/day, taking 3-4 minutes ,
And with a low-protein diet. Side effects are nausea , vomiting, tinnitus , visual disturbances .
2.Sodium phenylbutyrate (Buphenyl): in the liver may be oxidized to
phenylacetate, then combine and glutamine , the final product phenylacetylglutamine
Excreted in the urine . Every 1 mole of phenylbutyrate remove two moles of nitrogen. Given dose is 0.5
mg / kg / day.
3 Arginine (Arginine): via arginase enzyme (arginase) role after finishing each 1mole
Acid into 1mole of urea and ornithine 1mole (ornithine). Hyperammonemia circumstances,
Given dose of 600 mg / kg / day. Children with stable given oral doses of 400-700
m g / kg / day.
        Prognosis and age of diagnosis of illness related . In the neonatal period had symptoms of patients
, Its prognosis is poor , the majority of patients will have some significant complications . Require long-term with physicians
And nutritionists with continued outpatient follow , regular biochemical tests, recording height and weight development,
Grasp the patient's condition .

Citrullinemia reported cause of mental retardation in one case

Yang Bao patient , male , age 8 ,2012 -10-29 treatment. 3 years old to walk, still can not speak , only no destination is called , since the laugh , often bow to walk , life can not take care of themselves , do not know who , abnormal behavior , often while biting his right hand fingers, tapping with the left hand side of the body , I do not know with people play . Mother during pregnancy is no different, full-term birth . No special family history . Physical examination: good move, aimless running around , head appear before the triangle. High performance liquid chromatography - tandem mass spectrometry examination results citrulline (Cit52.9 ↑), glutamate / citrulline ratios : Glu / Cit 1.7 ↓. Liver and kidney function : alkaline phosphatase (ALP) 180 ↑, glandular dehydrogenase (ADA) ↑, blood urea nitrogen (BUN) 8.47 ↑, carbon dioxide (CO2-CP) 31 ↑, uric acid (UA) 477 ↑, β2 microspheres protein (β2-MG) 3.88 ↑. MRI: bilateral frontal poor leaf development . Because they do not fit unmeasured IQ. According to clinical manifestations judged as very severe behavioral disorders associated with mental retardation .
The final diagnosis: citrullinemia induced behavioral disorders associated with mental retardation
Discuss
Citrullinemia (citrullinemia, OMIM215700), by the McMurray et al ( 1963 ) found , is an autosomal recessive genetic disease, as arginyl acid enzyme deficiency , the enzyme gene is located on 9q34-qter. Metabolites in the body produce toxic effects on the human body of ammonia , ammonia through the urea cycle or ornithine cycle and detoxification. When urea cycle disorders can produce hyperammonemia . Urea cycle process requires six kinds of enzymes involved in , any of which can cause an enzyme defect urea cycle disorder caused by hyperammonemia . Under normal circumstances , citrulline and aspartate to form argininosuccinate . When argininosuccinate cleavage enzyme deficiency can not occur , then the accumulation of citrulline and ammonia to form citrullinemia pathological damage incurred , resulting in disease. The disease is divided into classic type Ⅰ and Ⅱ .
Citrullinemia type Ⅰ mostly onset shortly after birth , including feeding difficulties , frequent vomiting, convulsions , movement disorders , more than half survived the initial attack does not exceed 17 months , and ultimately died of cerebral edema, mostly in the infant deaths.
Citrullinemia usually in adult-onset type 2 , primarily affects the nervous system . Features include a mental disorder , abnormal behavior ( such as aggressive , allergies and hyperactivity ) , seizures and coma. More than before the onset of stress , infections, alcohol or food intake a lot of protein and other incentives , the disease progresses rapidly into a coma , also can be deadly.
The clinical features of children : severe mental retardation , mental and behavioral disorders, facial features appear before the head triangle, but early childhood feeding conditions and physical symptoms is unknown. The few cases reported in the literature of different higher cognitive dysfunction is prominent intellectual and mental disorders based. Visible genetic disease phenotype can vary greatly , which has a high degree of heterogeneity, clinicians should pay attention to .
The clinical diagnosis of the disease lack of clinical specificity , mainly by blood, urine levels of citrulline , arginine exception. Etiological diagnosis based succinic acid arginyl decreased activity , and genetic testing .
To reduce high blood ammonia toxic effects on the nervous system , shall be permanently adhere to a low -protein diet can give sodium benzoate , sodium phenylacetate reduce ammonia and symptomatic treatment. Arginine may improve mitochondrial urea cycle enzyme activity , it can also be used to reduce ammonia . The only effective treatment is still liver transplantation , but the quality of life for patients with post-transplant time and lack of relevant research, so the effect is hard to evaluate for liver transplantation .

Citrullinemia for liver regeneration oath when the big love

Mrs. Chen attended Taipei Veterans General Hospital today ( 4 ) , Mr. Day held for their successful operation press conference , through tears and said "My husband is really heavily built ."

  She said more than three years out of the hospital constantly with their husbands , because every time Chan with epilepsy onset , so has always been to " epilepsy " treatment, but no cause had been a long year, and finally in Taipei Veterans find out the cause , she first happy " can finally find out the cause of confrontation ," because when you can not find the cause , really helpless, she can cry the night .



But Mr. know on the liver transplant priority ranking is not optimistic , we need more cooperation, is still very worried . Thanksgiving Mrs. Chen said , they really are very fortunate to receive love to donate the liver, "Without the donated liver Buddha , I can not sit here today , Mr. , our family is no longer happy ." Chen wife said , so she and her husband have signed organ donation consent.



Auxiliary orthotopic liver transplantation in the world, some are still rare, and because citrullinemia liver transplantation in Taiwan have not yet heard , Taipei Veterans General Hospital , director of rare diseases Niu Tao Ming said , as chromosomes citrullinemia recessive genetic disease , that must be the parents of each with a mutated gene , with no clinical symptoms of carriers, but the next generation of every child , regardless of gender , 1/ 4 chance of suffering from this disease , there is neonatal onset and adult onset type] predilection 20-50 years old.



According to the prevalence estimate that Taiwan should have one case per twenty thousand people , that Taiwan has at least 1,100 cases , but in addition to other hospitals in the past few informed NTU , very few reported cases heard , Niu Ming said , because patients are suddenly lost consciousness after the onset of elevated blood ammonia or seizures, if not alert physicians often difficult to find the cause , so he suspected cases have been underestimated in Taiwan , I am afraid that many cases been delayed .



Niu Tao confessed, citrullinemia first to be discovered , most cases of Japan, according to Japanese physicians statistics, due to alcohol and high sugar foods can induce elevated blood ammonia , so citrullinemia patients will not consciously avoid alcohol and high-sugar diet, too much eating peanuts and other hydrocarbon-containing foods high in acid and in vivo acids can be combined with food , so can delay the onset of the time .



Cattle Dominicans reminder , alcohol , colds and other drugs cause illness and acetaminophen in patients with liver citrullinemia cumulative citrulline will speed up , so pay attention , but Mr. Chen transplanted normal metabolic function of the liver , to be implanted hyperplasia of the liver to normal size , he would not have to worry about this problem.

Thailand seeking to restore sea sick infant's life

Thailand a newborn that is, since the diagnosis of citrullinemia baby boy , due in critical condition, as a physician in the mother running under the sea to come to Taiwan for medical treatment , emergency imposed by the National Taiwan University Hospital hemodialysis, as well as giving exclusion ammonia drugs, lucky save a life.
National Taiwan University Hospital , director of gene therapy, Dr. Hu pointed out that the boy to come to Taiwan for medical expenses, hospital to give 30% discount roughly NT $ 60 to 700,000 yuan . Currently boy has returned to Thailand four months , the disease is still in control, still rely on every day can help eliminate ammonia and drug Buphenyl special formula milk , medication alone may take 3 to 4 month yuan.

National Taiwan University Hospital 's department of pediatrics Jane Ying show that citrullinemia is autosomal recessive metabolic disorder , is a rare disease , the incidence is about 2-3 births 1 ; mainly in the human body after eating protein metabolic process , can not effectively convert the toxic ammonia into non-toxic urea, citrulline accumulation and resulting hyperammonemia . Over the past eight years, the National Taiwan University Hospital screening of 24 sick children , but more severe as the first type citrullinemia , NTU also has a sick children currently waiting for a liver transplant .

Hu says , this newborn baby boy in the third day, ie vomiting, drowsiness, restlessness , shortness of breath , examination revealed blood ammonia over 500 units , must be urgently dialysis . Fortunately, the boy 's mother is immune to general practitioners , see NTU has published neonatal metabolic disorders undergoing hemodialysis papers , and thus sea to NTU for help.

National Taiwan University Hospital International CEO Ching-Ting Tan said that this name in the middle of the night wearing a respirator sick infants delivered by an aircraft Taoyuan airport, has shown signs of liver failure and respiratory failure, delivered directly by ambulance NTU .

National Taiwan University Hospital pediatrician Caiyi Rong said that the sick infants successfully placed double-lumen catheter , hemodialysis that night , after dialysis three times , and finally exclude ammonia , and in the special formula and rare disease drug treatment , the condition stabilized , nearly four weeks after hospitalization discharge return.

Citrullinemia, type II

Also known as:

• CIT II
• citrullinuria
• citrin deficiency
• CTLN II
• neonatal intrahepatic cholestasis caused by citrin deficiency (neonatal form only)
• NICCD (neonatal form only)
• citrullinemia

Citrullinemia, type II (CIT II) is a condition in which the body is unable to make citrin, a protein that helps move substances within the cells. These substances are important for breaking down sugars, producing proteins and nucleotides, and allowing for the normal function of the liver. CIT II is considered an amino acid condition because people with this condition are unable to transport certain amino acids into mitochondria, the energy-production centers of the cell. You may also hear CIT II called a urea cycle condition. This name is used to describe conditions that cause ammonia to accumulate in the bloodstream.

CIT II is not the same condition as citrullinemia, type I. Even though these conditions have similar names, they have different signs, outcomes, and treatments.  If you are looking for information about citrullinemia, type I, go to this page.

Follow-Up Testing

Your baby’s doctor may ask you if your baby is showing any of the signs of CIT II (see Early Signs, below).If your baby has certain signs, your baby’s doctor may suggest starting immediate treatment.

If your baby’s newborn screening result for citrullinemia (CIT II) was out of the normal range, your baby’s doctor or the state screening program will contact you to arrange for your baby to have additional testing.It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. An out-of-range result may occur because the initial blood sample was too small or the test was performed too early. However, as a few babies do have the condition, it is very important that you go to your follow-up appointment for a confirmatory test. Because the harmful effects of untreated CIT II can occur soon after birth, follow-up testing must be completed as soon as possible to determine whether or not your baby has the condition. 

Follow-up testing will involve checking your baby’s urine and blood samples for signs of citrullinemia. Harmful amounts of certain substances build up in the body when a child has an amino acid condition, so measuring the amounts of these substances in your baby’s body can help doctors determine if your baby has a condition. High amounts of citrulline in the blood might indicate that your baby has CIT II.Sometimes follow-up testing may also include testing a very small sample of skin.

Recognizing citrullinemia

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Citrullinemia is autosomal recessive metabolic disorder urea cycle disorders (autosomal recessive urea cycle disorder), because succinate spermine synthase gene mutations that cause citrulline (Citrulline) can not be caused by metabolic clinical illness.

Continuation of ornithine cycle (ie urea cycle) a text, then we talk about the ornithine cycle spermine synthase succinate exception arising citrullinemia (Citrullinemia). Ornithine cycle generally consists of four steps: ornithine and ammonia, CO2, forming citrulline; citrulline and ammonia, forming arginine; arginine hydrolysis to give urea and ornithine; ornithine participate in the second round of cycle. Please go back and review the details.

Citrullinemia (Citrullinemia) autosomal recessive genetic disease, in the final reason is two:
Metabolic acid citrulline spermine synthase (argininosuccinate synthetase, ASS) gene mutations (Mutations in the ASS gene cause type I citrullinemia), led to the first type citrullinemia (citrullinemia type-I, CTLN-1 ), the incidence rate of 1/57, 000;SLC25A13 mutations result (Mutations in the SLC25A13 gene are responsible for type II citrullinemia), leads to the second type citrullinemia (citrullinemia type-Ⅱ, CTLN-Ⅱ). SLC25A13 gene may encode proteins Citrin, Citrin Aspartate can be transported from the mitochondria to the cytoplasm, to make aspartic acid (Aspartate) and citrulline (Citrulline) in Argininosuccinate synthetase (ASS) catalyst for Argininosuccinate synthesis. When the lack of Citrin, the metabolism of urea convenience blocked, causing neonatal cholestasis (neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD) and type II citrullinemia (citrullinemia type-II, CTLN-Ⅱ), the incidence of the latter 1/100, 000 to 1/230, 000.
CTLN-1, CTLN-2 and NICCD clinical manifestations, diagnosis, treatment in order as follows:
 Citrullinemia type I (citrullinemia type I) citrullinemia type II (citrullinemia type II)ClinicalSuccinate due spermine synthase (Argininosuccinate synthetase, ASS) exception, the body can not metabolize citrulline, leading to accumulation of citrulline, ammonia and toxic metabolites in the blood (ammonia and other toxic substances to accumulate in the blood ). Hyperammonemia manifested as poor feeding, vomiting, seizures, loss of consciousness, a lack of energy (lethargy), ankle clonus, etc., and rapidly changing conditions, sometimes with severe neurological abnormalities, left untreated, serious complications deathEarly childhood onset of symptoms compared infancy light, but obviously this period common brain lesionsCitrin protein function due to defects caused more frequent in adults (adulthood)Neonatal onset citrullinemia (Neonatal Hepatitis Associated with Choletasis, NICCD): children often behave in an age before cholestasis, fatty liver, liver fibrosis, growth retardation, hepatomegaly, abnormal liver function, blood clotting factor lower, hemolytic anemia, hypoproteinemia, galactosemia, multi Hyperaminoacidemia, AFP level rise, showing a slight, so symptoms may disappear after treatment;-year-old, the hi high protein and high fat diet, high aversion sugar foods. Part NICCD in adult patients with stage due to certain drugs, infections, alcohol induced heavier type II citrullinemia appearAdult-onset citrullinemia (adult type II citrullinemia): occurs in 20 to 50 years old. Hyperammonemia due to repeated easily affect the central nervous system, causing C onfusion, abnormal behavior (including aggression, irritability, hyperactivity), memory loss, neuropsychiatric symptoms, pumping 'A', normal or mildly abnormal liver function, pancreatic trypsin secretion inhibin concentrations (pancreatic secretory trypsin inhibitor, PSTI), serum [threonine] / [serine] ratio increased, branched-chain amino acids (Val + Leu + Ile) / aromatic amino acids (Tyr + Phe) ratio decreasedDiagnostic methods detect ammonia, citrulline, other amino acids, liver function, based on but the diagnosis is dependent on examination of liver cells or skin fibroblasts succinate spermine synthase (ASS) activity in order to detect the patient's blood biochemistry value equals base, including ammonia, citrulline, other amino acids concentration detection (such as serum [threonine] / [serine], (Val + Leu + Ile) / (Tyr + Phe) ratio), PSTI concentration, liver function, But genetic testing to find SLC25A13 mutations basis point is confirmedTreatmentElevated blood ammonia Acute: within 24 hours of completion of hemodialysisPhenylacetate may assist platoon ammoniaShould be given high-calorie and low-protein diet (Low protein diets), to prevent brain pressure increases, monitoring ammonia value; should avoid infectionNeonatal onset: add fat-soluble vitamins, protein, sugar and diet containing medium-chain fatty acids (middle-chain triglycerides, MCT); due to the high calorie diet but increased NADH generation, affecting urea synthesis and stimulates citrate-malate transport , resulting in hyperammonemia, fatty liver, high triglycerides disease hyperlipidemia. Most of the symptoms can be relieved by 1 to 2 yearsAdult-onset type: oral arginine (arginine), sodium benzoate, sodium phenylacetate, etc. can reduce the ammonia concentration; reduce high-calorie and high-sugar diet, increased protein intake and other measures to improve hypertriglyceridemia. Avoid alcohol, because alcohol stimulate ADH activity in the liver, and promote the synthesis of NADH harmful substances.If the event of cerebral edema, then avoid using glycerol and fructose, to avoid increasing the NADH generation, further causing toxic substances produced; Mannitol is generally used to reduce brain pressure. Some patients may rely on liver transplantation (liver transplan t) to survive

Citrullinemia Type I

Synonyms: Argininosuccinate Synthetase Deficiency; ASS Deficiency; Argininosuccinic Acid Synthetase Deficiency; CTLN1; Citrullinemia, Classic

Jess G Thoene, MD

Active Emeritus Professor of Pediatrics
Director, Biochemical Genetics Laboratory
University of Michigan
Ann Arbor, Michigan

jthoene@umich.edu

Initial Posting: July 7, 2004; Last Update: August 11, 2011.

Go to:

Summary

Disease characteristics. Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form, a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of theaffected individuals.

Diagnosis/testing. Citrullinemia type I results from deficiency of the enzyme argininosuccinate synthase (ASS), the third step in the urea cycle, in which citrulline is condensed with aspartate to form argininosuccinic acid. Untreated individuals with the severe form of citrullinemia type I have hyperammonemia (plasma ammonia concentration 1000-3000 µmol/L). Plasma quantitative amino acid analysis shows absence of argininosuccinic acid and concentration of citrulline usually greater than 1000 µmol/L (normal: <50 activity="" all="" and="" argininosuccinate="" ass="" decreased.="" enzyme="" expressed="" fibroblasts="" i="" in="" is="" liver="" measured="" mol="" nbsp="" synthase="" tissues="" which="">ASS1

 is the only gene in which mutation is known to cause citrullinemia type I.

Management. Treatment of manifestations: Control of hyperammonemia using the Ucyclyd protocol of alternative means of waste nitrogen disposition (sodium benzoate and phenylacetate) or, if that protocol fails after two doses of medication, emergency use of hemodialysis; concomitant appropriate protein and calorie nutrition to prevent a catabolic state; steps to prevent increased intracranial pressure.

Prevention of primary manifestations: When solid foods are tolerated, oral administration of sodium phenylbutyrate and lifelong dietary management to maintain plasma ammonia concentration lower than 100 µmol/L and near-normal plasma glutamine concentration; L-carnitine to prevent systemic hypocarnitinemia. Liver transplantation has been reported.

Prevention of secondary complications: Medical attention during intercurrent infections to prevent hyperammonemia.

Surveillance: Routine follow up in a metabolic clinic; monitoring for hyperammonemia and secondary deficiency of essential amino acids; monitoring older individuals for signs of impending hyperammonia (i.e., mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus) and elevated plasma glutamine concentration.

Agents/circumstances to avoid: Excess protein intake; exposure to communicable diseases.

Evaluation of relatives at risk: Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete.

Genetic counseling. Citrullinemia type I is inherited in an autosomal recessive manner. At conception, each sib of an affectedindividual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of beingunaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

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Diagnosis

Clinical Diagnosis

Citrullinemia type I (CTLN1) results from deficiency of the enzyme argininosuccinate synthase, the third step in the urea cycle, in which citrulline is condensed with aspartate to form arginosuccinic acid (see Urea Cycle Disorders Overview Figure 1).

Classic neonatal-onset CTLN1 is suspected in infants who have been on a full protein diet and who present in the first week of life with:

• Hyperammonemia resulting in increasing lethargy, somnolence, refusal to feed, vomiting, and tachypnea or stroke. Initial plasma ammonia concentration in the severe form may be 1000-3000 µmol/L (normal: 40-50 µmol/L).
• Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus.

Milder, adult-onset citrullinemia type I is suspected in individuals with recurrent lethargy and somnolence; intellectual disability; and chronic or recurrent hyperammonemia. In these forms, a lower plasma concentration may be seen than in the classic form (adult upper limit of normal: <35 mol="" p="">

Testing

Plasma quantitative amino acid analysis

• Citrulline. Usually greater than 1000 µmol/L (normal: <50 li="" mol="">
• Argininosuccinic acid. Absent
• Arginine and ornithine. Low to normal range; see Urea Cycle Disorders Overview Figure 3.
• Lysine, glutamine, and alanine. Increased; these are surrogate markers of hyperammonemia.

Urinary organic acids. Normal, except orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry; however, the sensitivity depends on the extraction method.

Argininosuccinate synthase (ASS) enzyme activity. Incorporation of radiolabeled citrulline into argininosuccinic acid is measured in cultured fibroblasts. ASS activity is also determined by a method based on the conversion of radiolabeled (14C)-aspartate to (14C)-argininosuccinate [Gao et al 2003]:

• The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory.
• Cultured chorionic villus cells or cultured amniocytes from the fetus may be used for prenatal diagnosis.

Newborn screening. As of this writing, all states include CTLN1 in their newborn screening programs. Elevated citrulline is detected in dried blood spots on newborn screen by tandem mass spectroscopy (MS/MS). Citrullinemia is confirmed by plasma amino acid analysis that demonstrates the findings described above. Other conditions that may result in elevated citrulline on NBS are argininosuccinic acidemia, citrullinemia II (citrin deficiency), and pyruvate carboxylase deficiency.

Molecular Genetic Testing

Gene. ASS1 is the only gene in which mutations are known to cause citrullinemia type I.

Clinical testing

• Sequence analysis. Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication]. In Japan, a small number of mutations account for the majority of cases of CTLN1; however, a large number of mutations are found in individuals of European origin.
• Deletion/duplication analysis. Exonic and multiexonic deletions were reported by Engel et al [2009].
• Linkage analysis. An intragenic dinucleotide repeat is informative in 60%-70% of families.

Table 1. Summary of Molecular Genetic Testing Used in Citrullinemia Type I

Gene 1	Test Method	Mutations Detected 2	Mutation Detection Frequency by Test Method 3	Test Availability
ASS1	Sequence analysis	Sequence variants 4	96% 5	Clinical
	Deletion/duplicationanalysis 6	Exonic, multiexonic, or whole-genedeletions	Unknown
	Linkage analysis	Intragenic dinucleotide repeat	Informative in 60%-70%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. In 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%).

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependentprobe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a symptomatic proband

• The finding of elevated plasma ammonia concentration (>150; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) establishes the diagnosis of CTLN1. Note: Following the work up described in Urea Cycle Disorders leads to the diagnosis of citrullinemia type 1 when present. See Urea Cycle Disorders Overview Figure 3.
• Molecular genetic testing (sequence analysis of ASS1 followed by deletion/duplication analysis if neither or only onemutation is identified) may be helpful when the phenotype is unclear or biochemical values are borderline; it is especially helpful in distinguishing CTLN1 in its mild form from citrin deficiency.
  
  Note: (1) Determining the prognosis prospectively can be difficult in some individuals who fit the biochemical phenotype but may or may not have serious clinical illness. (2) Enzyme assay is not widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Linkage analysis can be considered for carrier testing if neither or only one mutation has been identified in an affected family member.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires either prior confirmation of enzyme deficiency in an affected family member or prior identification of the disease-causing mutations in the family. In certain instances, linkage analysis may be considered to improve prenatal testing accuracy if neither or only one mutation has been identified in an affected family member. Linkage must be established in the family before prenatal testing can be performed.

Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in ASS1.

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Clinical Description

Natural History

Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form, a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia.

In the acute neonatal form, the infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure [Brusilow & Horwich 2006]. Fifty-six percent of infants with classic citrullinemia type I are symptomatic by age four days and 67% by age one week [Bachmann 2003a].

Recently, two infants with classic CTLN1 with ammonia concentrations in the range of 400-500 µmol/L presented at age two and three months with cerebral infarcts [Choi et al 2006].

Children diagnosed and referred for appropriate treatment (see Management) survive for an indeterminate period of time, usually with significant neurologic deficits. All children with a peak plasma ammonia concentration greater than 480 µmol/L or an initial plasma ammonia concentration greater than 300 µmol/L have cognitive impairment [Bachmann 2003b]. The longest survival of an untreated infant with classic citrullinemia type I is 17 days.

In the late-onset form, the clinical course may be similar to or milder than that seen in the acute neonatal form, but for unknown reasons commences later in life. When episodes of hyperammonemia occur, they are similar to those seen in the acute neonatal form, but the neurologic findings may be more subtle because of the older age of the affected individuals. These can include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, and somnolence. Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [Brusilow & Horwich 2006]. Without prompt intervention, increased intracranial pressure occurs, with increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death.

Liver failure is being increasingly recognized as a primary presentation of CTLN1, contradicting established dogma of CNS symptoms as the primary findings. Two examples include:

• A 25-year old woman who presented with two episodes of acute liver failure, and who was ultimately shown to have CTLN1 by metabolite testing and molecular genetic testing [Salek et al 2010]
• A 15-month old female with CTLN1 who "...presented with encephalopathy and seizures with hyperammonemia requiring emergency treatment. Although there was a rapid resolution of her hyperammonemia, she developed fulminant liver failure. The severe increase of transaminases (aspartate aminotransferase and alanine aminotransferase levels peaking at 19,794 UI/L and 19,938 UI/L, respectively) and concurrent disturbances in her hepatic synthetic functions led to the consideration of a liver transplantation… " [Faghfoury et al 2011].

Pregnancy. Although a healthy woman with untreated CTLN1 underwent two successful pregnancies [Potter et al 2004], women with onset of severe symptoms during pregnancy or in the postpartum period have been reported [Gao et al 2003, Ruitenbeek et al 2003].

• Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery: one died and two survived without neurologic sequelae [Häberle et al 2009].
• CTLN1 has been implicated in postpartum psychosis [Häberle et al 2010].

Individuals remaining asymptomatic up to at least age ten years have been reported; it seems possible that they may remain asymptomatic lifelong [Häberle et al 2002, Häberle et al 2003].

Neuroimaging. CT scan of infants with citrullinemia type I demonstrates cerebral atrophy, particularly in the cingulate gyrus, the insula, and the temporal lobes, as well as general cortical hypo-attenuation (i.e., the cortex appears darker than in unaffectedindividuals) [Albayram et al 2002].

Genotype-Phenotype Correlations

Although certain mutations are identified with some phenotypes, the phenotype cannot be predicted in all instances [Engel et al 2009].

• Severe, classic citrullinemia type I typically results from 22 defined mutations [Engel et al 2009]. The mutation in exon 15, p.Gly390Arg, remains the most prevalent associated with the classic phenotype [Engel et al 2009, Laróvere et al 2009].
• Mild (i.e., late-onset) citrullinemia type I is associated with 12 mutations [Engel et al 2009].

Nomenclature

The preferred terms for argininosuccinic acid synthetase deficiency are "citrullinemia type I" and "classic citrullinemia," which are used to avoid confusion with the genetically distinct disease, citrullinemia type II, also known as citrin deficiency.

Prevalence

Citrullinemia type I occurs in 1:57,000 births and represented 74 of 545 (13.6%) individuals with urea cycle disorders referred to the Johns Hopkins Hospital from 1974 to 1994 [Brusilow & Horwich 2006].

Newborn screening programs found CTLN1 in the following:

• In Korea: two in 44,300 newborns [Yoon et al 2003]
• In New England: one in 200,000 newborns [Marsden 2003]
• In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence 1:118,543 [Niu et al 2010].
• In Austria: 1:77,811 among 622,489 newborns [Kasper et al 2010].

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Differential Diagnosis

Citrullinemia type II (CTLN2) is caused by citrin deficiency resulting from mutations in SLC25A13, which encodes the mitochondrial solute carrier protein, citrin. In citrin deficiency aspartate and glutamate fail to shuttle to and from the mitochondrion, leading to a mild hyperammonemia and citrullinemia. Mutation in SLC25A13 also leads to intrahepatic cholestasis in the neonate [Saheki & Kobayashi 2002]. The clinical course in adults with citrullinemia type II is milder than that of CTLN1, possibly distinguishing it from milder late-onset citrullinemia type I. It is not known why CTLN2 is milder and later in onset than CTLN1; distinguishing between the two disorders is difficult. The prevalence of citrullinemia type II has not been reported.

It is critical to distinguish hyperammonemia caused by a defect in the urea cycle from the secondary hyperammonemia caused by an organic acidemia (see Organic Acidemias Overview), which may cause inhibition of N-acetylglutamate synthase (see Urea Cycle Disorders Overview Figure 2).

Classic citrullinemia type I shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway. The mild phenotype shares a later onset with other disorders such as late-onset ornithine transcarbamylase (OTC) deficiency. Urea Cycle Disorders Overview Figure 3 shows a diagnostic strategy to identify which steps in the urea cycle are defective in an individual with hyperammonemia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

• Acute neonatal form
• Late-onset form

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Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with citrullinemia type I (CTLN1), the following evaluations are recommended:

• Measurement of: concentration of plasma ammonia, amino acids, and electrolytes; blood gases; urinary organic acids; and urinary orotic acid
• Assessment of intracranial pressure and overall neurologic status
• Genetics consultation

Treatment of Manifestations

Acute management of individuals with citrullinemia type I depends on early diagnosis, control of hyperammonemia, and control of intracranial pressure. Regular attendance at a metabolic clinic with access to a trained metabolic nutritionist is essential to proper management. See the American College of Medical Genetics  and  [www.acmg.net].

Ucyclyd protocol. The protocol designed by Brusilow and colleagues (Ucyclyd Pharma®) should be followed. This protocol uses alternative means of waste nitrogen disposition (sodium benzoate and phenylacetate). Buphenyl® (Ammonaps®) (oral form of sodium phenylbutyrate) is approved by the FDA. Sodium phenylacetate/sodium benzoate, 10% intravenous solution, received FDA approval as Ammonul® in February 2005.

Hemodialysis. Failure to control hyperammonia with the Ucyclyd protocol after two doses of medications described above requires emergency use of hemodialysis to reduce the plasma ammonia concentration to an acceptable level, following which institution of the sustaining infusion may be attempted, supplemented with additional doses over one hour as in the initial bolus infusion as needed to control plasma ammonia concentration [Lo et al 2003].

Diet. Concomitant with the Ucyclyd protocol, appropriate protein and calorie nutrition must be provided so that the affectedindividual does not become catabolic. In small infants, the 40 cal/100 mL given as D10W can be significant in averting catabolism. As soon as possible, osmolar load permitting, the individual should receive total parenteral nutrition (TPN) providing 0.25 g/kg/day of protein and 50 cal/kg/day, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/day of protein and 100-120 cal/kg/day. Standard TPN solutions of dextrose, aminosol, and intralipid are used.

Prevention of increased intracranial pressure. It is critical to monitor fluid balance, intake, and output and body weight, and to maintain the individual on the dry side of fluid balance: approximately 85 mL/kg of body weight per day in infants; appropriate corresponding fluid restriction in children and adults. Increased intracranial pressure is manifested by tension in the fontanel, acute enlargement of the liver, edema, and worsening neurologic signs including fisting, scissoring, ankle clonus, and coma. Cerebral edema and ischemia may be documented by MRI.

Prevention of Primary Manifestations

Medication. When the affected individual is able to tolerate solid food, the oral medication sodium phenylbutyrate (Buphenyl®, Ammonaps®), at a dose of 450-600 mg/kg/day divided into three doses, and arginine-free base of 400 and 700 mg/kg/day are begun. Success of therapy is defined by a plasma ammonia concentration lower than 100 µmol/L and near-normal plasma glutamine concentration. Plasma arginine concentration may be up to 250% above upper normal limit for age.

As children grow, doses change to 9.9-13 g/m2/day of sodium phenylbutyrate and 8.8-15.4 g/m2/day of arginine. For details of management, the reader is referred to Brusilow & Horwich [2006].

Treatment with L-carnitine has been advocated as auxiliary treatment to prevent systemic hypocarnitinemia, which may result from therapy with acylating agents.

Diet. Lifelong dietary management is necessary and requires the services of a metabolic nutritionist.

Liver transplantation. Liver transplantation for treatment of urea cycle disorders has been reported by several groups. Of sixteen individuals undergoing liver transplantation, 14 lived 11 months to six years post transplantation; their neurologic outcomes correlated closely with their pre-transplantation neurologic status. Few problems with long-term health were related to the liver transplantation itself and the quality of life was much improved [Whitington et al 1998].

A successful living related-donor liver transplantation (240 g) from mother to six-year-old daughter has been reported. The allopurinol challenge test was normalized in this child, who previously had very brittle control with four to six hyperammonemic episodes per year [Ito et al 2003].

A living related-donor liver transplantation from mother to son resulted in continued elevation in plasma concentration of citrulline (200-400µmol/L). The mother, a heterozygote, had 28% residual ASS 1 enzyme activity [Ando et al 2003].

A larger series of successful auxiliary partial liver transplants has been reported in CTLN type II [Yazaki et al 2004].

Prevention of Secondary Complications

Intercurrent infections (particularly some viral exanthems) may induce a catabolic state. Patients must be observed carefully during such episodes and medical attention sought to prevent hyperammonemia.

Surveillance

Appropriate monitoring of concentration of plasma amino acids to identify deficiency of essential amino acids as well as impending hyperammonemia is indicated.

Routine follow-up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required.

Monitoring for early warning signs of impending hyperammonic episodes including mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentration of glutamine and other surrogate markers is warranted in older individuals. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals [Brusilow & Horwich 2006].

Agents/Circumstances to Avoid

Avoid the following:

• Excess protein intake
• Obvious exposure to communicable diseases

Evaluation of Relatives at Risk

Because the long-term outlook for individuals with citrullinemia type I depends on initial and peak plasma ammonia concentration, it is important that at-risk sibs are identified as soon as possible. Current practice dictates either in utero diagnosis, which permits appropriate oral therapy beginning with first feeds, or measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because women with onset of severe symptoms during pregnancy or in the postpartum period have been reported, scrupulous attention needs to be paid to diet and medication during these periods.

Therapies Under Investigation

Gene therapy has been suggested; success has not been achieved to date.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Ketoacids of essential amino acids were an early form of auxiliary waste nitrogen disposal enhancement, now replaced by the agents described in Treatment of Manifestations.

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Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Citrullinemia type I (CTNL1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. One case of a heterozygote who developed cirrhosis has been reported [Güçer et al 2004].
• Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management).

Offspring of a proband. The offspring of an individual with citrullinemia type I are obligate heterozygotes (carriers) for a disease-causing mutation in ASS1.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible by molecular genetic test methods if both disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at 25% risk is possible. Methods of prenatal diagnosis:

• Argininosuccinate synthase enzyme activity is measured in uncultured fetal tissue obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or cultured amniocytes obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation.
  
  Note: (1) Improvement in diagnostic accuracy using the ratio of citrulline to ornithine and arginine concentrations in amniotic fluid has been reported [Chadefaux-Vekemans et al 2002]. (2) Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• Molecular genetic testing is possible for families in which both mutations have been identified in the family [Hong et al 2000, Hayakawa et al 2003].
  
  Note: In certain instances, linkage analysis may be considered to improve prenatal testing accuracy if neither or only onemutation has been identified in an affected family member. Linkage must be established in the family before prenatal testing can be performed.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

• National Library of Medicine Genetics Home Reference
  Citrullinemia
• Save Babies Through Screening Foundation, Inc.
  P. O. Box 42197
  Cincinnati OH 45242
  Phone: 888-454-3383
  Email: email@savebabies.org
  http://www.savebabies.org/
• Children Living with Inherited Metabolic Diseases (CLIMB)
  Climb Building
  176 Nantwich Road
  Crewe CW2 6BG
  United Kingdom
  Phone: 0800-652-3181 (toll free); 0845-241-2172
  Fax: 0845-241-2174
  Email: info.svcs@climb.org.uk
  www.climb.org.uk
• National Urea Cycle Disorders Foundation
  75 South Grand Avenue
  Pasadena CA 91105
  Phone: 800-386-8233 (toll-free); 626-578-0833
  Fax: 626-578-0823
  Email: info@nucdf.org
  www.nucdf.org
• Urea Cycle Disorders Consortium Registry
  Children's National Medical Center
  111 Michigan Avenue Northwest
  Washington DC 20010
  Phone: 815-333-4014
  Email: jseminar@cnmc.org
  Urea Cycle Disorders Consortium Registry

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Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Citrullinemia Type I: Genes and Databases

Gene Symbol	Chromosomal Locus	Protein Name	Locus Specific	HGMD
ASS1	9q34​.11	Argininosuccinate synthase	ASS1 @ LOVD	ASS1

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Citrullinemia Type I (View All in OMIM)

215700	CITRULLINEMIA, CLASSIC
603470	ARGININOSUCCINATE SYNTHETASE 1; ASS1

Normal allelic variants. ASS1 comprises 16 exons; the primary transcript is 1239 bp. Transcription starts at the 5' end of exon 3. In the homozygous state, mutations p.Trp179Arg, c.1168G>A, and p.Gly362Val are associated with mild or no clinical symptoms, as is heterozygosity for c.[323G>T]+[970+5G>A] [Häberle et al 2002]. At least 14 ASS1 pseudogenes are known.

Pathologic allelic variants. See Table 2. Engel et al [2009] defined 87 ASS1 mutations from all available ethnicities; 27 were previously undescribed. They were found to occur in most exons and several intervening sequences leading to abnormal mRNAsplicing. Seven mutations are associated with severe disease; three of them (p.Arg304Trp, c.421-2A>G, and p.Gly390Arg) account for the majority of citrullinemia type I [Gao et al 2003]. See Table A.

Table 2. Selected ASS1 Allelic Variants

DNA Nucleotide Change (Alias 1)	Protein Amino Acid Change	Reference Sequences
c.257G>A	p.Arg86His 2	NM_000050​.4 NP_000041​.2
c.323G>T 3	p.Arg108Leu 3
c.421-2A>G (IVS6-2A>G)	--
c.535T>C 3	p.Trp179Arg 2, 3
c.794G>A	p.Arg265His 2
c.910C>T	p.Arg304Trp
c.970+5G>A 3 (IVS13+5G>A)	--
c.1085G>T 3	p.Gly362Val 2, 3
c.1168G>A 3	p.Gly390Arg

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).

1. Variant designation that does not conform to current naming conventions

2. Associated with late-onset citrullinemia type I; see Genotype-Phenotype Correlations.

3. Variants associated with no clinical or mild clinical symptoms; see Table A.

Normal gene product. The translational product, argininosuccinate synthase, is a homotetramer of 186 kd. It catalyzes an essential reaction in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol, and requiring 1 mol of ATP.

Abnormal gene product. The argininosuccinate synthase enzyme is inactive or absent. Mutant ASS with abnormal KM(Michaelis constant) or very low ASS protein detected by ELISA using anti-ASS antibody (low CRIM: cross-reacting immunologic materials) has been found.

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References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page 

Literature Cited

1. Albayram S, Murphy KJ, Gailloud P, Moghekar A, Brunberg JA. CT findings in the infantile form of citrullinemia. AJNR Am J Neuroradiol. 2002;23:334–6. [PubMed]
2. Ando T, Fuchinoue S, Shiraga H, Ito K, Shimoe T, Wada N, Kobayashi K, Saeki T, Teraoka S. Living-Related Liver Transplantation for Citrullinemia: Different Features and Clinical Problems between Classical Types (CTLN1) and Adult-Onset Type (CTLN2) Citrullinemia. Japanese Journal of Transplantation. 2003;38:143–7.
3. Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr.2003a;162:410–6. [PubMed]
4. Bachmann C. Long-term outcome of patients with urea cycle disorders and the question of neonatal screening. Eur J Pediatr. 2003b;162 Suppl 1:S29–33. [PubMed]
5. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Available online. 2006. Accessed 6-26-13.
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Chapter Notes

Revision History

• 11 August 2011 (me) Comprehensive update posted live
• 2 June 2009 (me) Comprehensive update posted live
• 22 April 2008 (cd) Revision: deletion/duplication analysis available clinically
• 22 December 2006 (me) Comprehensive update posted to live Web site
• 7 July 2004 (me) Review posted to live Web site
• 9 February 2004 (jt) Original submission

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