Citrullinemia Type I 환자의 가족에서 발견된 새로운 Argininosuccinate Synthetase 유전자 돌연변이

안병환,김현정,박형두,김원덕 대한신생아학회 2010 Neonatal medicine Vol.17 No.2

Citrullinemia type I is an urea cycle defect caused by mutations in the argininosuccinate synthetase (ASS1) gene. We report a novel argininosuccinate synthetase gene mutation in a Korean family with type I citrullinemia. Metabolic evaluation revealed significant hyperammonemia. Amino acid/acylcarnitine screening using tandem mass spectrometry showed high level of citrulline. Plasma amino acid analysis showed high level of citrulline and the urine organic acid analysis showed makedly increased level of orotic acid. To confirm diagnosis of citrullinemia we did mutation analysis of the ASS1 gene. The patient was found to have mutations of c.689G>C (p.G230A) and c.892G>A (p.E298K), which were new types of argininosuccinate synthetase gene mutation have never been reported in Korea. We report a novel case of argininosuccinate synthetase 1 gene mutation and suggest that the gene study to the family members is necessary to carry out when a patient is diagnosed as citrullinemia. Citrullinemia는 요소 회로 이상으로 argininosuccinate synthetase의 결핍으로 기인한다. 저자들은 citrullinemia type I 환자와 그의 가족에서 새롭게 발견된 돌연변이를 경험하여 이를 보고하고자 한다. 환아는 광범위 신생아 선천성 대사이상 선별검사에서 citrulline이 고도의 증가 소견과 혈청 암모니아는982 μmol/L까지 증가 소견을 보였다. 혈청 아미노산 분석결과citrulline 1,581 nmol/mL로 현저한 증가 소견을 보였으며 또한소변 유기산 분석 검사결과 orotic acid가 3,566 mmol/mol Cr 로 매우 증가된 소견을 보였다. Citrullinemia 확진을 위하여 환아와 가족에 대하여 ASS1 gene 검사를 시행하였다. 환아는c.689G>C (p.G230A)와 c.892G>A (p.E298k)의 변이가 발견되어 ASS1 gene의 돌연변이에 의한 citrullinemia type I 으로 진단되었으며, 두 가지 돌연변이는 아직 국내에 보고된 적 없는 새로운 것으로 확인되었다. 국내에서 새롭게 발견된 citrullinemia type I 유전자를 보고하며 citrullinemia를 보인 경우 확진 및 유전상담을 위하여 가족 유전자 검사를 시행하는 것이 필요하다고 생각한다.

신생아기에 진단된 Citrullinemia 1례

송승규,오경창,홍미애,김희택,신혜정,김순영,장진근,조희승,김병일,양세원,최중환,Song, Seung Kyu,Oh, Kyung Chang,Hong, Mi Ae,Kim, Hee Taeg,Shin, Hye Jung,Kim, Soon Young,Chang, Jin Keun,Jo, Heui Seung,Kim, Beyong Il,Yang, Sei Won,Choi, J 대한소아청소년과학회 2002 Clinical and Experimental Pediatrics (CEP) Vol.45 No.4

Citrullinemia는 유전성 대사 질환 중 하나로서 argininosuccinic acid synthetase 결손에 의해 발생하는 질병이다. 구토, 기면 또는 보챔, 경련, 의식장애와 같은 증상이 고암모니아혈증에 의해 초래되고 고암모니아혈증을 신속히 치료해야만 비가역적인 뇌손상을 줄일 수 있다. 저자들은 소변 유기산 분석과 혈중 및 요중 아미노산 분석에 의해 citrullinemia 1례를 경험했기에 이에 문헌 고찰과 함께 보고하는 바이다. Citrullinemia is a rare inborn error of metabolism of the urea cycle, and was first reported by McMurray, et al. in 1962. It is inherited as an autosomal recessive trait. The normal synthesis of argininosuccinic acid is blocked in this disease due to a deficiency of argininosuccinic acid synthetase(AS), which has been demonstrated in liver cells and fibroblasts. The clinical symptoms are vomiting, lethargy or irritability, convulsion and mental retardation. The diagnosis is made by the finding of an increased plasma citrulline level. Every effort should be made to reduce the blood ammonia level as rapidly as possible before irreversible brain damage occurs. This report describes a case of citrullinemia that was diagnosed through organic acid analysis and amino acid analysis, and reviews the related literatures.

Nutritional Management in a Patient with Citrullinemia Type 1

( Hyejin Kang ),( Mihyang Kim ),( Ji Hyun Lee ) 한국임상영양학회 2021 Clinical Nutrition Research Vol.10 No.3

For patients with citrullinemia type 1, nutritional management is essential to prevent the occurrence of complications associated with hyperammonemia. This report describes a patient who had been receiving nutrition intervention for more than 3 years. A newborn diagnosed with hyperammonemia due to citrullinemia visited Ajou University Hospital and was referred to the nutrition team. After receiving acute treatment, the infant was regularly fed with specialized formula. A protein-restricted diet is recommended for maintaining normal development and achieving long-term survival. Through continuous provision of nutritional intervention, the child showed normal growth and development, and the energy-protein supply was maintained appropriately. This case clearly shows the importance of medical nutrition therapy for patients with citrullinemia.

Successful treatment of a child with citrullinemia

Key-Hyoung Lee,Moon-Sung Park,Si-Hoon Hahn 대한의학유전학회 1997 대한의학유전학회지 Vol.1 No.1

The amino acids formed by degradation of proteins ingested produce ammonia. The ammonia which is broken down end excreted as urea through a process known as the Kiebs-Hensleit cycle or the urea cycle (Rezvani, 1995). The urea cycle consists of five enzymes necessary for the synthesis of carbamyl phosphate, citrulline, argininosuccinate, arginine, and urea: carbomyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), and arginase (ARG) (Lloyd, 1992). Congenital deficiencies of the enzymes involved in the urea cycle are diseases that are almost fatal without treatment, showing symptoms like vomiting, lethargy, dyspnea, and coma due to hyperammonemia corning from the accumulation of ammonia and metabolic precursors resulting from the deficiency of one of these enzymes (Batshaw and Brusilow, 1983). Among these, the disease manifested by the congenital deficiency of argininosuccinate synthetase (AS) which is associated with the formation of argininosuccinate in citrulline is called argininosuccinate synthetase deficiency or citrullinemia. There have been two reports on this so for in Korea; one in July 1987 by Kim et al. and the other by Park et al. in 1995. We are to report a case of successful treatment of a child with citrullinemia who was transferred to our hospital due to dyspnea, lethargy, feeding difficulties, convulsions and cyanosis together with some document studies related to this case.

Successful treatment of a child with citrullinemia

Lee, Key-Hyoung,Park, Moon-Sung,Hahn, Si-Hoon Korean Society of Medical Genetics 1997 대한의학유전학회지 Vol.1 No.1

The amino acids formed by degradation of proteins ingested produce ammonia. The ammonia which is broken down and excreted as urea through a process known as the Klebs-Hensleit cycle or the urea cycle (Rezvani, 1995). The urea cycle consists of five enzymes necessary for the synthesis of carbamyl phosphate, citrulline, argininosuccinate, arginine, and urea: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), and arginase (ARG) (Lloyd, 1992). Congenital deficiencies of the enzymes involved in the urea cycle are diseases that are almost fatal without treatment, showing symptoms like vomiting, lethargy, dyspnea, and coma due to hyperammonemia coming from the accumulation of ammonia and metabolic precursors resulting from the deficiency of one of these enzymes (Batshaw and Brusilow, 1983). Among these, the disease manifested by the congenital deficiency of argininosuccinate synthetase (AS) which is associated with the formation of argininosuccinate in citrulline is called argininosuccinate synthetase deficiency or citrullinemia. There have been two reports on this so far in Korea; one in July 1987 by Kim et al. and the other by Park et al. in 1995. We are to report a case of successful treatment of a child with citrullinemia who was transferred to our hospital due to dyspnea, lethargy, feeding difficulties, convulsions and cyanosis together with some document studies related to this case.

Auxiliary partial orthotopic liver transplantation for adult onset type II citrullinemia

Bum Soo Kim,Sun Hyung Joo,Suk Hwan Lee,Jung Il Lee,Hyun Cheol Kim,남덕호,Ho Chul Park 대한외과학회 2011 Annals of Surgical Treatment and Research(ASRT) Vol.80 No.6

Adult-onset type II citrullinemia (CTLN2) is a disorder caused by an inborn error of metabolism affecting the liver. CTLN2 is an autosomal recessive disorder characterized by recurrent encephalopathy with hyperammonemia due to highly elevated plasma levels of citrulline and ammonia, caused by a deficiency of argininosuccinate synthetase in the liver. A small number of patients have undergone liver transplantation with favorable results. In Korea, the limitations of the deceased donor pool have made living donor liver transplantation a common alternative treatment option. We report the case of a patient with type II citrullinemia who was treated successfully with auxiliary partial orthotopic liver transplantation (APOLT) from a living donor. This is the first description of an APOLT for a patient with adult onset type II citrullinemia in Korea.

ASS 1 유전자 돌연변이로 확진된 시트룰린혈증 1형 1례

임대균,허림,권영희,이지은,조성윤,박형두,진동규,Yim, Dae kyoon,Huh, Rimm,Kwun, Younghee,Lee, Jieun,Cho, Sung Yoon,Park, Hyung Doo,Jin, Dong-Kyu 대한유전성대사질환학회 2015 대한유전성대사질환학회지 Vol.15 No.1

시트룰린혈증은 유전적인 요인에 의하여 혈중에 암모니아를 비롯한 독성 물질이 축적되어 치명적인 임상 경과를 나타낼 수 있는 질환이다. 이 질환은 2가지 형태로 구분할 수 있으며, 유형별로 각기 다른 원인과 임상 양상을 보이는 것으로 알려져 있다. 시트룰린혈증 1형은 상염색체 열성유전 질환으로 암모니아를 간에서 요소로 합성하는 과정에 아르기니노숙신 생성효소(argininosuccinate synthethase)가 결핍되어 혈중 암모니아 농도와 혈중 시트룰린 농도의 증가와 혈중 아르기닌의 저하를 초래하게 되는 질환이다. 시트룰린혈증의 유병률은 50,000-60,000명당 1명 정도이다. 시트룰린 혈증은 임상 양상과 분자유전학적 특징에 따라 2가지 유형으로 구분할 수 있는데, 1형은 급성으로 신생아기에 발병하는 가장 흔한 형태이다. 환자는 출생시에는 특별한 증상을 보이지 않다가, 생후 3-4일을 지나면서 구토, 기면, 발작을 나타내게 되며 심하면 혼수 및 사망까지 이를 수 있다. 한편, 발병이 늦은 경우는 보다 드문 형태로 임상적으로 비교적 경한 증상을 나타낸다. 시트룰린혈증 1형은 9q34.1 염색체에 위치한 ASS1 유전자의 돌연변이에 의하여 아르기니노숙신 생성효소가 결핍되어 나타나며, 이 효소는 요소 회로에서 시트룰린과 아스파르트산이 아르기니노숙신으로 전환되는 과정을 담당한다. 따라서 ASS1 유전자의 돌연변이를 규명하는 것은 이 질병을 진단하는 데 분자유전학적으로 가장 확실한 방법이다. 저자들은 의심 증상을 가진 환자에게 조기에 시트룰린혈증 1형을 유전자 분석을 통하여 진단하였으며, 지속적 신대체 요법을 포함한 효과적인 급성기 치료 과정을 거쳐 현재 장기적인 식이 및 약물 치료를 성공적으로 진행 중에 있어, 이를 문헌 고찰과 함께 보고하는 바이다. Citrullinemia type1 is an autosomal recessive disorder of the urea cycle characterized by neonatal or late onset of hyperammonemia caused by a deficiency of the enzyme argininosuccinate synthetase (ASS). An ASS1 deficiency demonstrates fatal clinical manifestations that are characterized by the neonatal metabolic coma and early death when untreated. It causes a broad spectrum of effects, ranging from a mild disorder to a severe mental retardation, epilepsy, neurologic deficits. An acute neonatal form is the most common. Infants are normal at birth followed by an acute illness characterized by vomiting, lethargy, seizures and coma. These medical problems are life-threatening in many cases. A later onset form is less frequent and may be milder than the neonatal form. This later-onset form is associated with severe headaches, visual dysfunction, motor dysfunction, and lack of energy. Citrullinemia type1 is caused by mutations in the ASS1 gene located on chromosome 9q34.1 that encodes argininosuccinate synthetase, the third enzyme of the urea cycle catalyzing the formation of argininosuccinic acid from citrulline and aspartic acid. The enzyme is distributed in tissues including liver and fibroblasts. This mutation leads to hyperammonemia, arginine deficiency and elevated citrulline level. In the urea cycle, argininosuccinate synthetase catalyses the conversion of citrulline and aspartate to argininosuccinate.. Here, we describe a female newborn patient with lethargy, rigidity and hyperammonemia who was diagnosed as citrullinemia type1 with a c.[421-2A>G], c.[1128-6_1188dup] mutation.

간질중첩증으로 발현한 시트룰린혈증 1례

장주영(Joo Young Jang),유수정(Su Jeong You),유한욱(Han-Wook Yoo),고태성(Tae-Sung Ko) 대한소아신경학회 2005 대한소아신경학회지 Vol.13 No.2

저자들은 14세 남아에서 고암모니아혈중과 이로인한 뇌증과 간질중첩증으로 발현한 시트룰린혈증을 경험하였기에 문헌고찰과 함께 보고하는 바이다. Status epilepticus and seizure in childhood have various etiologies. Metabolic disorders may be an important cause of seizure and status epilepticus in childhood. Citrullinemia is a form of urea cycle defects and usually presents as an overwhelming neonatal illness. But in mild forms of citrullinemia, patients shows a gradual onset with frequent vomiting and developmental delay. We experienced a case of a 14-year-old boy presenting status epilepticus and hyperammonemia. The diagnosis of citrullinemia was made based on the elevated serum citrulline(about 20 times of the normal), and blood ammonia(over 500 micromol/L) as well as mutation of argininosuccinate synthetase gene. Although hemodialysis was done to remove elevated ammonia, he was expired due to hyperammonemic encephalopathy and brain death. So we suggest that metabolic disorders should be considered as one of the etiologies of status epilepticus in childhood.

SLC25A13 유전자 돌연변이로 확진된 성인형 제 2형 시트룰린혈증 1례

정민섭,양아람,김진섭,박형두,이헌주,진동규,조성윤,Jeung, Min Sub,Yang, Aram,Kim, Jinsup,Park, Hyung-Doo,Lee, Heon Ju,Jin, Dong-Kyu,Cho, Sung Yoon 대한유전성대사질환학회 2016 대한유전성대사질환학회지 Vol.16 No.1

Adult-onset type II citrullinemia (CTLN2) is characterized by episodes of neurologic symptoms associated with hyperammonemia leading to disorientation, irritability, seizures, and coma. CTLN2 is distinct from classical citrullinemia, which is caused by a mutation of the argininosuccinic acid synthetase (ASS) gene. The serum citrulline level is elevated, while the activity of ASS in liver tissue is decreased. CTLN2 is known to have a poor prognosis if the proper treatment is not taken. We reported a female aged 37 years who developed recurrent attacks of altered consciousness, aberrant behavior, and vomiting. We initially suspected the patient had CTLN2 because of the signs of hyperammonemic encephalopathy, such as altered mentality, memory disturbance, and aberrant behaviors provoked by exercise-induced stress and excessive intravenous amino acid administration. Through her peculiar diet preferences and laboratory findings that included hyperammonemia and citrullinemia, we diagnosed the patient as CTLN2, and SLC25A13 sequencing revealed known compound heterozygous mutations (IVS11+1G>A, c.674C> A). Her parents were heterozygous carriers, and we identified that her older sister had the same mutations. The older sister had not experienced any episodes of hyperammonemia, but she had peculiar diet preferences. The patient and her sister have been well with conservative management. When considering the clinical course of CTLN2, it was meaningful that the older sister could be diagnosed early in an asymptomatic period and that preemptive treatment was employed. Through this case, CTLN2 should be considered in adults who present symptoms of hyperammonemic encephalopathy without a definite etiology. Because of its rare incidence and similar clinical features, CTLN2 is frequently misdiagnosed as hepatic encephalopathy, and it shows a poor prognosis due to the lack of early diagnosis and proper treatment. A high-carbohydrate diet, which is usually used to treat other urea cycle defects, can also exaggerate the clinical course of CTLN2, so proper metabolic screening tests and genetic studies should be performed. 성인기에 나타난 운동으로 인한 스트레스와 과량의 단백질 투여에 의한 의식 변화, 기억 장애, 행동 장애등의 고암모니아혈증성 뇌병증 소견을 토대로 저자들은 성인형 제 2형 시트룰린혈증을 의심하였다. 검사 결과에서 고암모니아혈증, 혈중 시트룰린 상승, 요중 오로트산 경도 상승을 보였으며, 이를 통해 성인형 제 2형 시트룰린혈증을 진단하였다. SLC25A13 유전자 분석 결과를 통해 환자에게서 복합 이형 접합성 돌연변이(IVS11+1G>A, c.674C>A)를 확인하였다. 환자의 가족에서도 유전자 분석 검사를 진행하였고, 아버지, 어머니, 남동생에게서 성인형 제 2형 시트룰린혈증 보인자를, 언니에게서 성인형 제 2형 시트룰린혈증 환자임을 확인하였다. 그 동안 보고된 성인형 제 2형 시트룰린혈증의 임상 경과를 고려했을 때, 증상이 없던 언니에게서 질환을 발견하고 보존적 치료를 선제적으로 시작함으로써, 신경학적 장애 없이 일상 생활을 영위하고, 추가적인 뇌 손상을 방지하기 위한 간 이식 등 장기적인 치료 계획을 수립했다는 점에서 의의가 있다. 본 환자의 증례를 통해 고암모니아혈증성 뇌병증이 발생한 성인에서, 간질환 및 뇌질환의 증거가 없으며 다른 뚜렷한 원인이 없는 경우에는, 성인형 제 2형 시트룰린혈증을 고려해야 한다는 점을 인지하였다. 빈도가 드문 질환이지만 간성 혼수로 흔히 오인되고 있으며, 조기 진단 및 적절한 치료가 이루어지지 않으면 비가역적인 신경학적 후유증이 발생할 수 있다. 또한 다른 요소 회로 대사 질환 및 간성 혼수와는 달리, 고탄수화물 식이가 질병의 경과를 인위적으로 악화시킬 수 있기에 적절한 대사 이상 검사 및 유전자 검사가 시행되어야 하겠다. 본 증례는 반복적인 고암모니아혈증성 뇌병증 소견을 보인 37세 여성과 뇌병증 소견이 없었던 언니에게서 성인형 제 2형 시트룰린혈증을 진단하고, 즉각적인 치료를 통해 심각한 신경학적 장애 없이 일상 생활을 지속하고 있는 환자들을 문헌 고찰과 함께 보고하는 바이다.

Case Report : The first successful live birth following preimplantation genetic diagnosis using PCR for type 1 citrullinemia

( Jae Hyun Cho ),( Chung Hoon Kim ),( Kyung Hee Lee ),( Il Kyung Jeon ),( Jae Min Kim ),( Byung Moon Kang ) 대한산부인과학회 2014 Obstetrics & Gynecology Science Vol.57 No.3

Type 1 citrullinemia (CTLN1) is an autosomal recessive inherited metabolic disorder caused by anargininosuccinicnate synthetase deficiency. The patient was a 38-year-old Korean woman who is a carrier for CTLN1 and her first baby was diagnosed with CTLN1. Preimplantation genetic diagnosis (PGD) for CTLN1 in day 3 embryos using polymerase chain reaction was performed for live birth of healthy baby who is no affected with CTLN1. One unaffected blastocyst was transferred. This resulted in a clinical pregnancy and the live birth of healthy male twin. They were confirmed to be unaffected with CTNL1 by post natal diagnosis. This is the first case report of the use of PGD for CTNL1.