Aciduria argininosuccínica: informe de un caso de inicio neonatal / Argininosuccinic aciduria: Neonatal case report

Los defectos del ciclo de la urea son enfermedades metabólicas hereditarias que se producen por defecto en una de las enzimas encargadas de la desintoxicación del amonio, lo que genera su acumulación en el organismo. Las manifestaciones clínicas pueden presentarse en la etapa neonatal, con morbimortalidad elevada, o de forma tardía. La heterogeneidad de los síntomas y la falta de sospecha clínica en neonatos conducen a un diagnóstico erróneo y se puede confundir con sepsis neonatal o hemorragias cerebrales. El aumento de amonio plasmático en el examen bioquímico orienta su diagnóstico hacia un defecto del ciclo de la urea.La aciduria argininosuccínica es el tercer defecto más frecuente del ciclo de la urea y es causada por deficiencia de la enzima argininosuccínico liasa. Se presenta el informe de un caso de inicio neonatal. Los objetivos son enfatizar en su sospecha diagnóstica y proponer herramientas diagnósticas tempranas, como su incorporación a la pesquisa metabólica neonatal.

Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle.Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

Genetic diagnosis of a Chinese pedigree affected with neonatal argininosuccinic aciduria / 中华医学遗传学杂志

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.

Intron mutations of argininosuccinate lyase (ASL) gene exist in a family with argininosuccinic aciduria / 临床检验杂志

Objective@#To perform gene detection and gene mutation analysis in a family with inherited metabolic diseases characterized as increased citrulline (Cit) by the MS/MS assay. @*Methods@#The peripheral blood samples were collected from the family members, and genomic DNA was extracted for gene diagnosis, which was performed by the whole exon sequencing method. The novel mutation gene was cloned into pcDNA3.1(+) vector, and its pathogenicity was verified by the Mini-gene assay in cultured cells in vitro. @*Results@#The clinical diagnosis of the proband as argininosuccinic aciduria (ASA) was clear. Two pathogenic mutations, c.281G＞T (p.Arg94Leu) and c.208-15 T＞A, were detected in the argininosuccinate lyase (ASL) gene, and they were not reported previously. The Mini-gene expression in vitro confirmed that c.208-15 T＞A could cause aberrant splicing, resulting in the retention of 13 bp in intron 2. @*Conclusion@#Two new pathogenic mutations of ASL gene, c.208-15 T＞A and c.281G＞T, are found in an ASA family, which enriches the mutation profile of ASL gene. The Mini-gene assay is a simple and effective tool for the research of intron mutations.

Neonatal hyperammonemia and citrullinemia caused by argininosuccinate lyase gene mutations / 中华围产医学杂志

ObjectiveTo analyze the characteristics of neonatal hyperammonemia and citrullinemia caused by argininosuccinate lyase (ASL) gene mutations, and to have a better understanding of this disease. MethodsA neonatal patient with the onset of hyperammonemia and citrullinemia admitted to the Department of Pediatrics of Peking University First Hospital on April 2, 2014, was retrospectively studied. Peripheral blood leukocyte DNA of the patient and his parents was collected to detectASS1,ASL andSLC25A13 gene mutations. The literature related to neonatal hyperammonemia, citrullinemia and argininosuccinic aciduria was reviewed. ResultsThe baby in this case appeared lethargic, had weaker crying and food refusal since three days after birth, and analysis of blood amino acid found a marked increase in blood ammonia (1 332μmol/L) and a significant rise in citrulline (759.12μmol/L). Sanger sequencing detection revealed compound heterozygous mutations in theASL gene (c.434 A>G, c.857A>C) and this c.857A>C mutation was the first reported case in China. This case of hyperammonemia and citrullinemia was confirmed as argininosuccinic aciduria caused by ASL gene mutations. A protein-limited diet and the treatment of arginine and L-carnitine were given. His blood ammonia decreased to normal level and there was a significant improvement in physical and intellectual progress at five months old. Unfortunately, he had an intestinal infection when he was over five months old and the blood ammonia level tested in the local hospital was 480μmol/L. Gradually there was a disturbance of consciousness, then coma, and he finally died after active rescue in the local hospital.ConclusionsHyperammonemia and citrullinemia in neonates are likely to be argininosuccinic aciduria and a gene mutation test may be helpful for diagnosis.

A case of neonatal death due to argininosuccinic aciduria / 临床儿科杂志

Objectives To report the ifrst Chinese case of early onset argininosuccinic aciduria. Methods A girl aged three days was admitted because of vomiting and lethargy from the second day of life. General laboratory examination, blood amino acids analysis, urine organic acids tests and gene studies were performed for the diagnosis. Results Severe hyperam-monemia, liver dysfunction, metabolic acidosis, hypokalemia and hypocalcemia were found. Bood citrulline was extremely elevated (1098.12μmol/L vs normal range 5 to 25μmol/L), while blood arginine was decreased. Urine orotic acid, uracil and argininosuccinic acid were signiifcantly elevated. Two known heterozygosis mutations on ASL gene, c.544C>T (p.R182X) and c.706C>T (p.R236W), conifrmed the diagnosis of argininosuccinic aciduria. Unfortunately, protein-restricted diet with L-arginine supplement showed no effect. The patient died at the 23th day of life. Conclusions Argininosuccinic aciduria is a severe inherit-ed metabolic disorder. Clinical diagnosis is dififcult. It is characterized biochemically by severe citrullinemia. Urine organic acids analysis and ASL gene analysis are important for the differential diagnosis. In this study, a case of neonate death due to early-on-set argininosuccinic aciduria was diagnosed by post-mortem investigation. ASL gene study is helpful for the genetic counseling and prenatal diagnosis of the disease.

The First Neonatal Case of Neonatal Argininosuccinic Aciduria in Korea

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.