Objective: The study is a retrospective review which provides preliminary data on the correlation between biochemical profiles and initial clinical manifestation of patients diagnosed to have argininosuccinate synthetase deficiency (ASSD) and argininosuccinate lyase deficiency (ASLD) detected by expanded newborn screening (ENBS). Methods: This is a study of five distal UCD patients initially detected by elevated citrulline on ENBS. Medical charts of the patients were reviewed. The initial clinical manifestations of the patients were correlated with results of biochemical tests. Results: There were four cases of ASLD and one case of ASSD reviewed in this study. All cases of ASLD were confirmed by the presence of argininosuccinic acid (ASA) in the urine metabolic screen (UMS). The plasma citrulline level of the ASSD patient is significantly elevated as compared to the ASLD patients (2,690 µmol/L; NV: 10-45 µmol/L). The ASSD patient and one ASLD patient were symptomatic within the first six days of life. Both presented with significantly elevated plasma ammonia, citrulline and glutamine levels. Three ASLD patients were asymptomatic on initial screening. Conclusion ENBS has shown importance in the early detection and management of ASSD and ASLD. Early initiation of management may prevent hyperammonemic crises. Long term outcome studies are needed to look into the correlation of neurodevelopmental outcome with lifelong accumulation of citrulline and glutamine in ASSD and ASA in ASLD.
Citrullinemia ; Argininosuccinic Aciduria ; Argininosuccinic Acid

Argininosuccinic aciduria is an inborn error of the urea cycle caused by deficiency of argininosuccinate lyase (ASL). ASL-deficient patients present with progressive intoxication due to accumulation of ammonia in the body. Early diagnosis and treatment of hyperammonemia are necessary to improve survival and prevent long-term handicap. Two clinical phenotypes have been recognized--neonatal acute and milder late-onset form. We investigated patients with hyperammonemia by a stepwise approach in which quantitative amino acids analysis was the core diagnostic procedure. Here, we describe the clinical phenotypes and biochemical characteristics in diagnosing this group of patients. We have identified 13 patients with argininosuccinic aciduria from 2003 till 2009. Ten patients who presented with acute neonatal hyperammonemic encephalopathy had markedly elevated blood ammonia (> 430 micromol/L) within the first few days of life. Three patients with late-onset disease had more subtle clinical presentations and they developed hyperammonemia only during the acute catabolic state at two to twelve months of age. Their blood ammonia was mild to moderately elevated (> 75-265 micromol/L). The diagnosis was confirmed by detection of excessive levels of argininosuccinate in the urine and/or plasma. They also have moderately increased levels of citrulline and, low levels of arginine and ornithine in their plasma. Two patients succumbed to the disease. To date, eleven patients remained well on a dietary protein restriction, oral ammonia scavenging drugs and arginine supplementation. The majority of them have a reasonable good neurological outcome.
Age of Onset ; Amino Acids/analysis ; Argininosuccinic Acid/blood ; Argininosuccinic Acid/urine ; Argininosuccinic Aciduria/*diagnosis ; Argininosuccinic Aciduria/*metabolism ; Argininosuccinic Aciduria/*physiopathology ; Malaysia ; Phenotype

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

OBJECTIVE: To analyze the clinical and genetic features of two children suspected for arginylsuccinuria aciduria. METHODS: The patients were subjected to high-throughput sequencing using a gene panel. RESULTS: Both patients had high citrulline (87.37-156.10 μmol/L) measured by mass spectrometry/mass spectrometry (MS/MS) upon neonatal screening but had no symptoms. Two compound heterozygous variants of the ASL gene were detected in patient 1 (exon 6: c.467C>T inherited from her father and exon 7: c.556C>T inherited from her mother), among which c.556C>T is novel. Patient 2 had mental retardation and two full siblings who had died of hyperammonemia. Two compound heterozygosity variants of the ASL gene were detected (exon 3: c.281G>T inherited from his father and intron: c.208-15T>A inherited from his mother). Both were novel mutations. CONCLUSION Variants of the ASL gene probably underlie the argininosuccinic aciduria in the two patients. Above findings have enriched the spectrum of ASL mutations.
Argininosuccinic Aciduria ; Child ; Female ; Genetic Testing ; Humans ; Hyperammonemia ; Infant, Newborn ; Neonatal Screening ; Tandem Mass Spectrometry

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

We describe our initial experience of the perioperative anesthetic care provided to 8 years old female child with argininosuccinic acidemia undergoing living-related liver transplantation because it is the only available therapy for end-stage liver disease. Induction and maintenance of anesthesia has been conventional method. Arterial catheterized at radial and femoral arteries for continuous blood pressure monitoring and sampling. 18 G central vein catheterization was placed in left subclavian vein for fluid, drug infusion and CVP monitoring. EKG, pulse oxymetry, end-tidal CO2, urine output and body temperature were monitored. CBC, PT, aPTT, serum electrolyte were checked at preanhepatic, anhepatic phase and just after hepatic artery anastomosis. ABGA was checked every 1 hour. The level of serum ammmonia returned to normal range without protein restriction. We describe this case and a brief review of the literature.
Anesthesia* ; Argininosuccinic Aciduria* ; Blood Pressure Monitors ; Body Temperature ; Catheterization ; Catheters ; Child ; Electrocardiography ; Female ; Femoral Artery ; Hepatic Artery ; Humans ; Liver Diseases ; Liver Transplantation* ; Liver* ; Reference Values ; Subclavian Vein ; Veins