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

Urea cycle disorders are characterized by encephalopathy, respiratory alkalosis, and hyperammonemia. A urea cycle disorder should be considered a diagnostic possibility in any patient regardless of age with occult encephalopathy. The most common central nervous system pathology of urea cycle disorder is cerebral edema. The cerebral edema is caused by astrocyte swelling secondary to hyperammonemia and intracellular glutamine accumulation. Strokes in children occur in conjunction with cardiac disease, hematologic disorders, mitochondrial encephalopathy, trauma, intracranial infections and migraines. Recently, several inborn errors in metabolism have been recognized as possible causes of stroke. To our knowledge, there have been several reports on ornithine transcarbamylase deficiency with stroke. However, the case of citrullinemia presenting with a stroke-like episode has not been described previously. We report two infantile cases of citrullinemia with initial presentation of stroke. The differential diagnosis of unexplained strokes should include inborn errors of urea cycle metabolism during childhood.
Alkalosis, Respiratory ; Astrocytes ; Brain Edema ; Central Nervous System ; Child ; Citrullinemia* ; Diagnosis, Differential ; Glutamine ; Heart Diseases ; Humans ; Hyperammonemia ; Metabolism ; Migraine Disorders ; Mitochondrial Diseases ; Ornithine Carbamoyltransferase Deficiency Disease ; Pathology ; Stroke* ; Urea ; Urea Cycle Disorders, Inborn

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

Humans ; Urea Cycle Disorders, Inborn/diagnosis* ; Ornithine Carbamoyltransferase Deficiency Disease/diagnosis* ; China

Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (<i>Ni>-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.
Humans ; Child ; Citrullinemia/drug therapy* ; Urea Cycle Disorders, Inborn/therapy* ; Arginine ; Sodium Benzoate/therapeutic use* ; Liver Transplantation

Citrullinemia is an autosomal recessive disorder resulting in a deficiency of the urea cycle enzyme, argininosuccinate synthetase, which is mainly found in the liver. Despite the improvement in a dietary therapy during the past 20 years for the treatment of urea cycle disorders with the systematic adjunction of sodium benzoate, sodium phenylbutyrate and arginine, the overall outcome of severe forms of hyperammonemia often remains disappointing. As the liver is the only organ in which ammonia is transformed into urea, liver transplantation has been considered as an elegant and radical alternative therapy to classical dietetic and medical therapy. A child with classical citrullinemia was treated at age 34 months by a living related liver transplantation. The levels of plasma and urinary citrulline decreased slightly after transplantation, but serum ammonia levels and amino acid concentrations returned to the normal range without protein restriction. We describe this case and include a brief review of the literature.
Ammonia ; Anesthesia* ; Arginine ; Argininosuccinate Synthase ; Child ; Citrulline ; Citrullinemia* ; Humans ; Hyperammonemia ; Liver Transplantation* ; Liver* ; Plasma ; Reference Values ; Sodium ; Sodium Benzoate ; Urea ; Urea Cycle Disorders, Inborn

Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.
Base Sequence ; Carbamoyl-Phosphate Synthase (Ammonia)/chemistry/*genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease/diagnosis/*genetics ; Codon, Nonsense ; Exons ; Female ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Republic of Korea ; Sequence Analysis, DNA ; Urea Cycle Disorders, Inborn/diagnosis

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

Hyperammonemia in the newborn often leads to severe fatal illness associated with hyperammonemic encephalopathy. Transient hyperammonemia in newborns (THAN) is characterized by self-limiting, transient hyperammonemia during the neonatal period. THAN may have favorable long-term outcomes if it is diagnosed early and appropriately managed. However, severe hyperammonemia can develop even in newborns with THAN, which may require emergent management. Here we report a case of THAN with severe hyperammonemia during the neonatal period that was successfully treated with continuous renal replacement therapy and nitrogen-scavenging medications. Our patient went on to develop normally and has not re-experienced a hyperammonemic episode until 9 months of age without the administration of a protein restricted diet or medications.
Diet, Protein-Restricted ; Humans ; Hyperammonemia ; Infant, Newborn ; Renal Replacement Therapy ; Urea Cycle Disorders, Inborn

OBJECTIVENeonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, MIM#605814) is an inherited metabolic disease resulting from mutations of the gene SLC25A13, which encodes citrin, a liver-type mitochondrial aspartate-glutamate carrier. Mutation analysis is necessary for definitive diagnosis of NICCD patients. So far (March, 2007), 36 kinds of mutation, including 7 nonsense, 10 missense, 11 abnormal splicing, 4 insertion and 4 deletion, have been identified by Kobayashi's group, who cloned the gene in Kagoshima, Japan. To date, most of the NICCD patients reported in the world are Japanese. This study aimed to explore the gene diagnosis procedure of two known SLC25A13 mutations in a pedigree with an NICCD patient from China.

METHODSDNA was extracted from dried blood spots collected with filter papers from the proband and other 9 members in a NICCD pedigree from China, and then PCR amplification and agarose gel electrophoresis were performed, revealing two mutations preliminarily, which were further proved by Genescan, a procedure established in our laboratory already. Furthermore, the positions and characteristics of the mutations were finally confirmed by DNA sequencing.

RESULTSThe proband is a compound heterozygote of two mutations, 851-854del in exon 9 and 1638-1660dup in exon 16 of SLC25A13 gene. His mother and brother carry the former mutation, which predicts a frameshift and introduction of a stop codon at position 286, while his father, one aunt and her son carry the latter, resulting in a frameshift at codon 554, and introducing a stop codon at position 570.

CONCLUSIONA deletion mutation 851-854del in exon 9 and an insertion mutation 1638-1660dup in exon 16 of SLC25A13 gene were identified in the pedigree, providing reliable evidences for both diagnostic confirmation of the patient and the genetic counseling from other members in the pedigree.

Calcium-Binding Proteins ; deficiency ; genetics ; metabolism ; China ; Cholestasis ; etiology ; genetics ; Cholestasis, Intrahepatic ; genetics ; metabolism ; Citrullinemia ; complications ; genetics ; DNA Mutational Analysis ; Genetic Testing ; Hepatocytes ; Humans ; Infant ; Japan ; Liver Diseases ; genetics ; Male ; Membrane Transport Proteins ; Mitochondrial Membrane Transport Proteins ; genetics ; Mutation ; Organic Anion Transporters ; deficiency ; genetics ; Pedigree ; Urea Cycle Disorders, Inborn ; genetics