I. What is Citrin Deficiency Disease? Citrin deficiency disease is a disease in which the body, mainly in the liver, does not make the protein called “Citrin” properly. The symptoms of Citrin Deficiency Disease are completely different in childhood and in adulthood, so they are referred to by the following names. Children (especially infants): Neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency) Adults: Adult onset citrullinemia type II: CTLN2 (adult- onset type II citrullinemia) onset type II citrullinemia) II. What are the manifestations of Citrin deficiency disease? *** Infancy/NICCD *** Children with NICCD may present with yellow urine, persistent yellowing of the skin and sclera (jaundice), frequent feeding, poor weight gain, or deficiency. The diagnosis can be confirmed by more detailed tests (blood, ultrasound, liver biochemistry, genetic tests). In our country, many people are misdiagnosed with cytomegalovirus (CMV) hepatitis. Treatment can be done with special formula and symptomatic drugs. There are also cases where the symptoms disappear on their own without any treatment. However, the use of targeted treatment will greatly accelerate the pace of improvement while potentially reducing the chances of progression to liver failure. **** Infant? School age? Adolescence*** Although there may be a period of time when the disease does not appear to be present, some patients may develop the characteristics and symptoms described below. One of the characteristics is a partial diet, with some foods being very popular and others being very unpopular. They tend to prefer high protein and high fat foods such as beans (tofu, beans), eggs, cheese, salad dressings, etc., but not sugary foods such as fruits, juices, desserts, etc., which are generally popular among children. In addition, there are children who hate bread and rice. This characteristic is thought to be a physical response to deal effectively with illness. Do not reprimand your child for being “too picky and disobedient” and do not indiscriminately force him/her to eat the same foods (especially sugary foods) as everyone else. They may also have the following symptoms: easy fatigue, lethargy, low blood sugar, frequent diarrhea, diagnosis of pancreatitis due to abdominal pain, or seizures. **** Adolescence? Adulthood: CTLN2 **** CTLN2 exhibits completely different symptoms from NICCD. CTLN2 may manifest as sudden forgetting how to get home, not knowing what you are doing, loss of consciousness, irritability, and seizures. The diagnosis can be made based on elevated ammonia and citrulline in the blood. Nowadays, liver transplantation is the confirmed effective treatment. Early detection through regular checkups is expected to avoid liver transplantation through medication. Recently, some problems have been identified in the previously used medical treatment of CTLN2. Because CTLN2 causes hyperammonemia, symptomatic treatment often involves low protein foods, high energy fluids, and anti-cerebral edema drugs, but these treatments may worsen CTLN2 symptoms. Not all patients with Citrin deficiency disease (2 SLC25A13 gene abnormalities) will develop CTLN2, and it is possible to live a healthy life. It is now believed that the development of this disease is related to lifestyle habits and hormonal effects. However, the exact cause is still unknown and is currently under investigation. Important points to note ** About diet** As mentioned above, patients with citrin deficiency disease have a special diet that is based on an aversion to sugary foods. This can be seen as a response to the body’s struggle with citrin deficiency. It is better to talk to the school teacher in advance and tell them that your child “may not be able to eat the same food as others at school”. ** About alcohol consumption** Most patients are generally not allowed to drink alcohol. It is necessary to be careful because alcohol consumption can be a trigger for the onset of the disease. Next, hospitals and doctors should be aware that patients with citrinosis may suffer from other illnesses, such as respiratory infections, or may undergo surgery as a result of an accident. In such cases, medical staff should be aware of the following: In patients with citrinosis, the use of large amounts of high-concentration glucose solutions (high-energy infusions, glycerin injections, etc.) can cause symptoms to worsen, which is dangerous. Of course, patients and their families should also keep this in mind, and it is important to make this clear to doctors and hospitals. This can be considered an important part of disease prevention measures. (In addition, it is thought that in pediatrics, etc., there is no need to be concerned about low-concentration glucose drips of about 5% for the treatment of vomiting, diarrhea, and hypoglycemia.) Why do I get sick (genetic aspects)? A brief explanation of genetic problems is given here. If you would like a more detailed explanation, please consult with your doctor or a genetic counselor. The human body is made up of many kinds of proteins. Genes are like the design drawings of various proteins, written in a script called DNA. Citrin is also an important protein, mainly in the liver, and the design of Citrin is called the SLC25A13 gene (the notation of the gene is difficult to understand and is referred to here as the citrin gene), and each person carries two copies of the design of the citrin gene. One is from the father and the other from the mother. These genes (design drawings) are often written incorrectly (called variants or mutations in genetics). In the case of Citrin deficiency disease, if only one of the two blueprints is incorrectly written and the other is not abnormal, the person will not get sick (this state is called a carrier). Since carriers have no symptoms, it is impossible to know who is a carrier without testing the gene. The majority of parents of Citrin deficiency patients are carriers, and the father and mother of a Citrin deficiency patient are carriers of both the normal gene [A] and the faulty gene [a], denoted by Aa. The probability of inheritance of a child born to two parents with the same Aa gene is: two normal AA 1/4 carriers with one normal and one faulty Aa 1/2 carriers with two faulty aa aa 1/4 carriers with two faulty aa genes (mutant purets), who are unable to produce functional citrin, resulting in Citrin deficiency disease. Such a form of inheritance is called autosomal recessive inheritance. An actual survey of the frequency of Citrin mutations showed that the same mutations were detected in the Chinese as in the Japanese, especially in the area south of the Yangtze River in China, with a carrier rate of 1 in 40. However, it is not clear whether NICCD and CTLN2 occur in all mutation-pure individuals. V. What is Citrin? Citrin is a functional protein embedded in the inner membrane of mitochondria, called aspartate (Asp)-glutamate (Glu) carrier. citrin deficiency disease, the lack of aspartate in the cytoplasm of the liver, and the reduction of energy production in mitochondria, so that weight gain is poor and fatigue is easy. VI. The need for long-term follow-up There is still a lot of uncertainty about this disease (Citrin deficiency disease). In order to better understand this disease, it is necessary to conduct long-term follow-up. ① Avoiding dangerous treatment of the disease due to misdiagnosis of other diseases, ② Using internal medication instead of liver transplantation and appropriate food therapy, ③ Taking measures to prevent the occurrence of serious diseases