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.