OBJECTIVE: To explore the genetic basis of a neonate with argininosuccinic aciduria (ASA). METHODS: A neonate with lethargy and food refusal was admitted. The patient had myoclonus, myasthenia, uroschesis, irregular breathing and paroxysmal ventricular tachycardia, and died at 75 hours after birth. Laboratory test showed marked increase in blood ammonia (1249.8 μmol/L). Peripheral blood samples of the patient, her parents and sister were collected and subjected to trio whole-exome sequencing. RESULTS: Whole-exome sequencing revealed that the patient has carried compound heterozygous mutations of the argininosuccinate lyase (ASL) gene, namely c.425(exon5)_c.426(exon5) insAGCTCCCAGCT (p.Thr142Thrfs*37) and c.626(exon8)delT (p.Leu209Argfs*42). The patient was diagnosed as ASA caused by ASL gene mutations. Her parents and her elder sister were heterozygous carriers of the above mutations and had a normal phenotype. CONCLUSION ASA is a severe congenital genetic metabolic disease and can manifest as onset of hyperammonemia in neonates. The clinical diagnosis is difficult and ASL gene testing may be helpful.
Argininosuccinate Lyase ; genetics ; Argininosuccinic Aciduria ; diagnosis ; genetics ; Female ; Genetic Testing ; Humans ; Hyperammonemia ; Infant, Newborn ; 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

Argininosuccinic aciduria (ASAuria) is a rare autosomal recessive urea cycle disorder. Neonatal presentation of ASAuria is the most common form. It is characterized by lethargy, feeding intolerance, decreased consciousness, and coma after 24 to 72 hours of birth. We describe a rare case of ASAuria in a female neonate who presented with severe hyperammonemia, a typical characteristic of urea cycle disorders. This patient's diagnosis was confirmed by biochemical analyses, and we found that the patient had a point mutation of the argininosuccinate lyase gene, which was homozygous for a novel 556C>T substitution. We have never seen the neonatal form of ASAuria in Korea. Therefore, this is the first report of neonatal onset ASAuria in Korea.
Argininosuccinate Lyase ; Argininosuccinic Aciduria ; Coma ; Consciousness ; Female ; Humans ; Hyperammonemia ; Infant, Newborn ; Korea ; Lethargy ; Parturition ; Point Mutation ; Urea Cycle Disorders, Inborn

OBJECTIVETo detect potential mutations of Y9ASS1, ASL and SLC25A13 genes in four patients manifesting citrullinemia.

METHODSGenomic DNA was extracted from peripheral blood leukocytes. Exons and their flanking sequences of the three genes were amplified with polymerase chain reaction and subjected to direct DNA sequencing.

RESULTSBased on DNA sequence analysis, one case was diagnosed with argininosuccinate synthetase deficiency, and the mutation type (ASS1 gene) was c.236C>T (p.S79F) + c.431C>G (p.P144R). Two cases were diagnosed with argininosuccinic aciduria (ASL gene), and their gene mutations were c.434A>G (p.D145G) + c.1366C>T (p.R456W) and c.331C>T (p.R111W) + IVS8+2insT, respectively. A thirteen months boy who carried a heterozygous 851del4 mutation (SLC25A13 gene) was diagnosed with citrullinemia adult-onset type II.

CONCLUSIONThrough analysis of relevant pathogenic genes, four patients have been diagnosed.

Adult ; Amino Acid Sequence ; Argininosuccinate Lyase ; genetics ; metabolism ; Argininosuccinate Synthase ; genetics ; metabolism ; Base Sequence ; Citrullinemia ; enzymology ; genetics ; Female ; Humans ; Infant ; Male ; Mitochondrial Membrane Transport Proteins ; genetics ; metabolism ; Molecular Sequence Data ; Pedigree ; Point Mutation

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. 1) 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). 2) 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. 3) 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. 4) and the other by Park et al. 5) 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.
Amino Acids ; Ammonia ; Arginase ; Arginine ; Argininosuccinate Lyase ; Argininosuccinate Synthase ; Carbamyl Phosphate ; Child* ; Citrulline ; Citrullinemia* ; Coma ; Cyanosis ; Dyspnea ; Humans ; Hyperammonemia ; Korea ; Lethargy ; Ligases ; Ornithine Carbamoyltransferase ; Seizures ; Urea ; Urea Cycle Disorders, Inborn ; Vomiting

OBJECTIVETo investigate the value of the determination of the levels of serum argininosuccinate lyase (ASL) in diagnosing various liver diseases.

METHODSTwo hundred and ninety-one patients with various liver diseases, 257 patients with non-liver disease, and 32 healthy controls were recruited for this study and their serum ASL, ALT, AST, GGT, LDH, ALP, and total bilirubin (TBil) levels were determined. Liver biopsies were performed on 31 patients with hepatopathy.

RESULTSReceiver operating characteristic (ROC) curve analysis showed that the sensitivity and specificity of ASL in assessing liver diseases were 100% and 91.1% (at cut-off values of 8 U/L), those of ALT were 97.6% and 24.7% and those of AST were 83.8% and 28.3% (both at cut-off values = 40.0 U/L), respectively. The levels of ASL in various liver disease patients were: in liver cancer - acute hepatitis - liver cirrhosis - chronic hepatitis. A positive correlation (r = 0.417) was observed between serum ASL levels (86.9+/-26.5) and scores of histopathological inflammation grading (9.83+/-3.36).

CONCLUSIONASL is of higher sensitivity and specificity than those of ALT and AST for diagnosing liver diseases. ASL may be used as a useful marker in estimating hepatopathy.

Adolescent ; Adult ; Aged ; Argininosuccinate Lyase ; blood ; Automation ; Female ; Humans ; Liver Diseases ; blood ; diagnosis ; Male ; Middle Aged ; ROC Curve ; Sensitivity and Specificity ; Serum ; chemistry ; Young Adult