A deficiency of the urea cycle enzyme, argininosuccinate synthetase which is produced in liver, makes citrullinemia, which is an autosomal recessive disorder. As the liver is the only organ which transforms ammonia into urea, liver transplantation has been considered as an effective alternative therapy to classical dietary and medical therapy. We have experienced perioperative anesthetic care for a 27-year-old male with citrullinemia undergoing successful living donor auxiliary partial orthotopic liver transplantation (APOLT). After the liver transplantation, the postoperative clinical courses of the patient were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly without any kinds of protein dietary restrictions. We present this case with a brief review of literature.
Adult ; Ammonia ; Argininosuccinate Synthase ; Citrulline ; Citrullinemia ; Humans ; Hyperammonemia ; Liver ; Liver Transplantation ; Living Donors ; Male ; Plasma ; Urea

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.
Argininosuccinate Synthase ; Citrulline ; Citrullinemia ; Humans ; Hyperammonemia ; Korea ; Mass Screening ; Orotic Acid ; Plasma ; Tandem Mass Spectrometry ; Urea

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.
Argininosuccinate Synthase ; Citrulline ; Citrullinemia ; Humans ; Hyperammonemia ; Korea ; Mass Screening ; Orotic Acid ; Plasma ; Tandem Mass Spectrometry ; Urea

OBJECTIVE: To analyze the clinical and genetic characteristics of three Chinese pedigrees affected with Citrullinemia type I (CTLN1). METHODS: Three children diagnosed at the Children's Hospital Affiliated to Shandong University from 2017 to 2020 were selected as the study subjects. Genomic DNA was extracted from peripheral blood samples of the probands and their parents. Next generation sequencing (NGS) was carried out to detect pathological variants of the probands. Sanger sequencing was used for validating the candidate variant among the pedigrees. RESULTS: The probands have respectively carried compound heterozygous variants of c.207_209delGGA and c.1168G>A, c.349G>A and c.364-1G>A, c.470G>A and c.970G>A of the ASS1 gene, which were respectively inherited from their parents. CONCLUSION The newly discovered c.207_209delGGA and c.364-1G>A variants have enriched the mutational spectrum of the ASS1 gene. And the mutation spectrum of Chinese CTLN1 patients is heterogeneous.
Child ; Humans ; Argininosuccinate Synthase/genetics* ; Citrullinemia/genetics* ; East Asian People ; Mutation ; Pedigree

Arginine deprivation is a novel antimetabolite strategy for the treatment of arginine-dependent cancers that exploits differential expression and regulation of key urea cycle enzymes. Several studies have focused on inactivation of argininosuccinate synthetase 1 (ASS1) in a range of malignancies, including melanoma, hepatocellular carcinoma (HCC), mesothelial and urological cancers, sarcomas, and lymphomas. Epigenetic silencing has been identified as a key mechanism for loss of the tumor suppressor role of ASS1 leading to tumoral dependence on exogenous arginine. More recently, dysregulation of argininosuccinate lyase has been documented in a subset of arginine auxotrophic glioblastoma multiforme, HCC and in fumarate hydratase-mutant renal cancers. Clinical trials of several arginine depletors are ongoing, including pegylated arginine deiminase (ADI-PEG20, Polaris Group) and bioengineered forms of human arginase. ADI-PEG20 is furthest along the path of clinical development from combinatorial phase 1 to phase 3 trials and is described in more detail. The challenge will be to identify tumors sensitive to drugs such as ADI-PEG20 and integrate these agents into multimodality drug regimens using imaging and tissue/fluid-based biomarkers as predictors of response. Lastly, resistance pathways to arginine deprivation require further study to optimize arginine-targeted therapies in the oncology clinic.
Arginase ; Arginine ; Argininosuccinate Lyase ; Argininosuccinate Synthase ; Biomarkers ; Carcinoma, Hepatocellular ; Drug Combinations ; Epigenomics ; Glioblastoma ; Humans ; Kidney Neoplasms ; Lymphoma ; Melanoma ; Sarcoma ; Urea ; Urologic Neoplasms

OBJECTIVETo detect potential mutations in six patients with citrullinemia.

METHODSGenomic DNA was extracted from peripheral blood samples from the patients. Mutations of the ASS1, ASL and SLC25A13 genes were screened using microarray genotyping combined with direct sequencing.

RESULTSOne patient was diagnosed with argininosuccinate lyase deficiency, and has carried a homozygous c.1311T>G (p.Y437*) mutation of the ASL gene. The remaining five patients were diagnosed with neonatal intrahepatic cholestasis due to citrin deficiency, and have respectively carried mutations of the SLC25A13 gene including [c.851-854delGTAT+c.851-854delGTAT], [c.851-854delGTAT+IVS6+5G>A], [c.851-854delGTAT+IVS16ins3kb], [c.851-854delGTAT+IVS6-11A>G] and [c.851-854delGTAT+c.1638-1660dup23]. Among these, the c.1311T>G mutation was first identified in the Chinese population, and the IVS6-11A>G mutation was a novel variation which may affect the splicing, as predicted by Human Splicing Finder software.

CONCLUSIONThis study has confirmed the molecular diagnosis of citrullinemia in six patients and expanded the mutational spectrum underlying citrullinemia.

Argininosuccinate Lyase ; genetics ; Argininosuccinate Synthase ; genetics ; Citrullinemia ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation

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.
Adolescent ; Ammonia ; Argininosuccinate Synthase ; Brain Death ; Citrullinemia* ; Diagnosis ; Humans ; Hyperammonemia ; Male ; Renal Dialysis ; Seizures ; Status Epilepticus* ; Urea ; Vomiting

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.
Adult ; Ammonia ; Argininosuccinate Synthase ; Citrulline ; Citrullinemia ; Humans ; Hyperammonemia ; Korea ; Liver ; Liver Transplantation ; Living Donors ; Plasma ; Tissue Donors

OBJECTIVETo identify the genetic mutation in ASS1 gene in a Chinese family with citrullinemia typeI, which may provide a basis for the diagnosis and genetic counseling.

METHODGenomic DNA was isolated from peripheral blood samples of the family members. Mutation analysis of ASS1 gene was carried out by PCR and Sanger sequencing. Biostructural analysis of the mutated ASS1 was completed by Phyre server.

RESULTDouble heterozygous mutations in the proband were identified: c.951delT (F317LfsX375) and c.1087C>T (R363W), which were confirmed in the proband's father and mother, respectively. It was found that the c.951delT mutation might change the formation of a dimer or a tetramer and the function of ASS1 protein.

CONCLUSIONDouble heterozygous mutations for c.951delT and c.1087C>T have been found in a proband with citrullinemia typeI. The c.951delT is a novel mutation in citrullinemia typeI, which may change the configuration of ASS1 protein and result in ASS1 dysfunction.

Argininosuccinate Synthase ; genetics ; Asian Continental Ancestry Group ; genetics ; Citrullinemia ; genetics ; DNA Mutational Analysis ; Humans ; Infant, Newborn ; Mutation

Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant disease, which has an extremely low survival rate of <9% in the United States. As a new hallmark of cancer, metabolism reprogramming exerts crucial impacts on PDAC development and progression. Notably, arginine metabolism is altered in PDAC cells and participates in vital signaling pathways. In addition, arginine and its metabolites including polyamine, creatine, agmatine, and nitric oxide regulate the proliferation, growth, autophagy, apoptosis, and metastasis of cancer cells. Due to the loss of argininosuccinate synthetase 1 (ASS1) expression, the key enzyme in arginine biosynthesis, arginine deprivation is regarded as a potential strategy for PDAC therapy. However, drug resistance develops during arginine depletion treatment, along with the re-expression of ASS1, metabolic dysfunction, and the appearance of anti-drug antibody. Additionally, arginase 1 exerts crucial roles in myeloid-derived suppressor cells, indicating its potential targeting by cancer immunotherapy. In this review, we introduce arginine metabolism and its impacts on PDAC cells. Also, we discuss the role of arginine metabolism in arginine deprivation therapy and immunotherapy for cancer.
Arginine/metabolism* ; Argininosuccinate Synthase ; Carcinoma, Pancreatic Ductal/drug therapy* ; Cell Line, Tumor ; Humans ; Pancreatic Neoplasms/drug therapy*