Type II citrullinemia in an elderly patient treated with living related partial liver transplantation.
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A 60-year-old woman was admitted to our hospital for repeated consciousness disturbance. Blood examination showed hyperammonemia, and plasma amino acid analysis revealed a marked increase in the citrulline level. To establish a diagnosis, a percutaneous needle biopsy of the liver was performed. The determination of the urea cycle enzyme activities revealed a selective marked decrease in argininosuccinate synthetase activity, indicating the final diagnosis of type II citrullinemia. The mean survival period of this disease after the appearance of symptoms has been reported as 26.4 months, and most conservative treatments are not effective. We performed a living related partial liver transplantation. Over the subsequent 13-month follow-up, the patient's condition has remained fairly good. (+info)
Mutation analysis of Korean patients with citrullinemia.
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Citrullinemia is an autosomal recessive disease due to the mutations in the argininosuccinate synthetase (ASS) gene. Mutation analysis was performed on three Korean patients with citrullinemia. All of the three patients had the splicing mutation previously reported as IVS6-2A>G mutation. Two had Gly324Ser mutation and the other patient had a 67-bp insertion mutation in exon 15. The IVS6-2A>G mutation was reported to be found frequently in Japanese patients with citrullinemia, but Caucasian patients showed the extreme mutational heterogeneity. Although a limited number of Korean patients were studied, the IVS6-2A>G mutation appears to be one of the most frequent mutant alleles in Korean patients with citrullinemia. The Gly324Ser mutation identified in two patients also suggests the possible high frequency of this mutation in Korean patients as well. (+info)
Reversibility of serum NH3 level in a case of sudden onset and rapidly progressive case of type 2 citrullinemia.
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A 48-year-old male presented with an acute change in mental status due to a marked elevation of plasma NH3 and was diagnosed with citrullinemia with amino acid analysis of blood. Hemodialysis and hemodiafiltration were performed, but serum chemical analysis did not show any improvement which led us to terminate dialysis following intensive care for 3 days. Surprisingly, NH3 level had decreased by 6 days after admission, coinciding with normalization of the size of the pupils. Since spontaneous remission had never been discussed, we discuss this relatively rare, but clinically significant entity with regard to its acute phase management and its potential reversibility. (+info)
Correction of argininosuccinate synthetase (AS) deficiency in a murine model of citrullinemia with recombinant adenovirus carrying human AS cDNA.
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Citrullinemia is an autosomal recessive disorder caused by the deficiency of argininosuccinate synthetase (AS). It is characterized by elevated levels of blood citrulline and ammonia, which often results in hyperammonemic coma and early neonatal death in affected children. We have explored the use of adenoviral vectors as a treatment modality in a murine model of citrullinemia, the Ass mouse. The Ass mouse has no endogenous AS activity due to a targeted interruption of the AS gene. Homozygous mutant animals develop high levels of blood citrulline, become hyperammonemic, and die within 24-48 h after birth. We demonstrated that the neonatal crisis in Ass mice can be ameliorated by the injection of a recombinant adenovirus carrying human AS cDNA (Ad.CMVhAS) within hours after birth. The average life span of the virus-treated animals was extended from 30 +/- 9.5 h to 16.1 +/- 1.6 days. A second viral infusion 14 days after the first dose further prolonged the life span to an average of 36.2 +/- 7.0 days, and to 40.7 +/- 3.3 days with a concurrent daily injection of arginine and sodium benzoate. Significantly increased liver AS activity (47.3 +/- 7.9% of normal) was detected 24 h after viral infusion, which reached peak levels (80-90% of normal) at day 7 and decreased to about 20% of normal within 2-3 weeks after viral infusion. Southern blot analysis of liver DNA revealed a transduction efficiency of about one viral genome per hepatocyte 7 days after viral infusion and a gradual decrease of viral genome per cell parallel to the loss of liver AS activity. Plasma glutamine levels were partially normalized in virus-treated animals and were completely normalized in animals receiving Ad.CMVhAS concurrently with alternative pathway therapy. Plasma arginine levels were also partially normalized. Together, these results demonstrated that the recombinant adenovirus was capable of conferring AS activity in the liver of the recipient animals within 24 h, and the neonatal crisis of hyperammonemia could be averted by acute treatment with the AS containing adenovirus. (+info)
The first successful prenatal diagnosis on a Korean family with citrullinemia.
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DNA prenatal diagnosis was successfully performed on a family with citrullinemia. The father carried the G324S mutation and the mother carried the IVS6-2A > G mutation in the argininosuccinate synthase gene. They had a previous child with citrullinemia who died in the week after birth owing to complicated hyperammonemia. The lost child turned out to be a compound heterozygote. DNA was extracted from the cultured amniotic cells after amniocentesis done at 18-week gestation. For the detection of the G324S mutation, the PCR and restriction fragment length polymorphism method was used, and for the IVS6-2A > G mutation, allele-specific PCR was performed. The fetus was found to carry G324S but not IVS6-2A > G, suggesting a heterozygote carrier. Pregnancy was continued and a healthy boy was born. Plasma amino acid analysis performed on the third day after birth was normal and the serial ammonia level was in the normal range. A molecular study on his genomic DNA after birth also agreed with the previous fetal DNA analysis. He is now 2-months old with normal growth and development. (+info)
Localized proton MR spectroscopy in infants with urea cycle defect.
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SUMMARY: Urea cycle defect is an inborn error of ammonium metabolism caused by a deficient activity of the enzymes involved in urea synthesis. Localized short-TE proton MR spectroscopy, performed in two infants who had citrullinemia and ornithine transcarbamylase deficiency, respectively, showed a prominent increase of glutamine/glutamate and lipid/lactate complex in both cases. N-acetylaspartate, total creatine, and myo-inositol were decreased in the infant with citrullinemia. Proton MR spectroscopy provided useful information for the diagnosis and understanding of the pathophysiology of urea cycle enzyme defect. (+info)
Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria.
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The mitochondrial aspartate/glutamate carrier catalyzes an important step in both the urea cycle and the aspartate/malate NADH shuttle. Citrin and aralar1 are homologous proteins belonging to the mitochondrial carrier family with EF-hand Ca(2+)-binding motifs in their N-terminal domains. Both proteins and their C-terminal domains were overexpressed in Escherichia coli, reconstituted into liposomes and shown to catalyze the electrogenic exchange of aspartate for glutamate and a H(+). Overexpression of the carriers in transfected human cells increased the activity of the malate/aspartate NADH shuttle. These results demonstrate that citrin and aralar1 are isoforms of the hitherto unidentified aspartate/glutamate carrier and explain why mutations in citrin cause type II citrullinemia in humans. The activity of citrin and aralar1 as aspartate/glutamate exchangers was stimulated by Ca(2+) on the external side of the inner mitochondrial membrane, where the Ca(2+)-binding domains of these proteins are localized. These results show that the aspartate/glutamate carrier is regulated by Ca(2+) through a mechanism independent of Ca(2+) entry into mitochondria, and suggest a novel mechanism of Ca(2+) regulation of the aspartate/malate shuttle. (+info)
A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia.
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Citrullinaemia is an inborn error of metabolism resulting from a deficiency of argininosuccinate synthetase. Previous studies of RNA of argininosuccinate synthetase of citrullinaemia patients using S1 nuclease analysis have identified a class of so-called RNA-negative alleles in which no stable mRNA can be detected. To investigate the nature of mutation responsible for such a phenotype, a compound heterozygous citrullinaemia carrying an RNA-negative allele and an allele with a 3' splice site mutation in intron 6 (IVS6-2A>G) was analysed. Using sequences of a DNA polymorphism and the IVS6-2A>G mutation as markers, approximately equal amounts of pre-mRNAs from allelic genes were detected suggesting that RNA-negative phenotype could not be the result of defect in transcription initiation. A C-to-T transition converting the CGA arginine codon at residue 279 to a TGA termination codon (R279X) was identified by cDNA sequencing. No accumulation of partially spliced pre-mRNAs containing introns immediately upstream and downstream of the nonsense mutation was observed. In addition, no mRNA species of abnormal size was detected when cDNA from the RNA-negative allele was analysed. Hence, there is no indication of nonsense-associated altered splicing (NAS). The most likely event responsible for the RNA-negative phenotype appears to be nonsense-mediated mRNA decay (NMD). (+info)