Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Citrullinemia”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2003

Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1).

Citrullinemia is caused by either deficiency of argininosuccinate synthetase (ASS, citrullinemia type 1) or a defect of the SLC25A13 gene encoding a mitochondrial aspartate-glutamate transporter (citrullinemia type II). Citrullinemia type 1-referred to as classical citrullinemia-is characterized by largely elevated concentrations of citrulline, manifesting with acute hyperammonemic crises predominantly early in life and occurs panethnically. Citrullinemia type II is a rare multisystem-disorder nearly exclusively observed in the Japanese population and characterized by less pronounced elevations of plasma citrulline and mainly a late onset of clinical symptoms. Here, we investigated 21 citrullinemic patients (mean peak plasma citrulline 1023 micromol/l, range 152-3360), all of whom remained asymptomatic during the observation period (6-156 months). These patients were referred to as mild citrullinemia due to less striking peak citrulline concentrations or absent clinical symptoms. Extended newborn screening using tandem mass spectrometry detected 15/21 patients, 4/21 patients were identified by investigation of siblings, 2/21 during metabolic work-up of unspecific neurological symptoms. We characterized the genetic defects in all affected families and found all patients affected by citrullinemia type 1 due to mutations of the ASS gene. We identified 15 different mutations, 14/15 missense and 1/15 nonsense, 6/15 were novel mutations. This is the first genetic study in a series of patients with hitherto asymptomatic citrullinemia. According to the mutations found in this study, mild citrullinemia seems to be primarily related to the human ASS gene, at least in patients of caucasian origin.

Alleles↗
PubMed2006

Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia.

BACKGROUND: In the course of 25 years, we have experienced a high rate of affected fetuses in the prenatal diagnosis of citrullinemia. METHODS AND RESULTS: Ninety-one pregnancies at 1 in 4 risk were tested; 36 were diagnosed as affected (39.5%; P = 0.0015). The high rate of positive diagnoses was found both after chorionic villus sampling (24/68 = 35.3%) and amniocentesis (12/23 = 52.2%) despite the completely different and independent techniques used. Using exactly the same (indirect) enzyme assay for argininosuccinic aciduria on chorionic villi and a similar method on amniotic fluid, the expected rate of affected fetuses was found: 13/53 = 24.5%. Technical and genetic causes for the unexpected results were excluded by confirmatory studies performed on independent fetal material, which was available for 27 of the 36 fetuses affected with citrullinemia. Biochemical confirmation was obtained in the 27 cases, whereas in 18 fetuses homozygosity or compound heterozygosity for disease-causing mutations were retrospectively demonstrated in the stored fetal cells. CONCLUSION: The results suggest the occurrence of preferential transmission of the mutant allele. An explanation for this phenomenon may be found in a protective role of argininosuccinic acid synthetase deficiency in mutant sperm cells against the possibly detrimental or apoptotic effect of nitric oxide produced normally from arginine by nitric oxide synthase.

Amniocentesis↗
PubMed1995

Pancreatic secretory trypsin inhibitor gene is highly expressed in the liver of adult-onset type II citrullinemia.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS is deficient specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there are no apparent abnormalities in the amount, translational activity, and nucleotide sequence of hepatic ASS mRNA. Recent results of homozygosity testing indicate that the primary defect of type II citrullinemia is not within the ASS gene locus. In this present work, to understand the pathogenesis and pathophysiology of type II citrullinemia, we have characterized the alterations of gene expression in the liver of type II patients using the recently developed mRNA differential display method. Some cDNA bands expressed differently in type II citrullinemia patients and control were selected, cloned, and sequenced. Nucleotide sequence analysis and homology searching revealed an interesting clone which has 99% homology with the human pancreatic secretory trypsin inhibitor (hPSTI). Northern blot and RT-PCR analyses showed that the expression of hPSTI mRNA increased significantly in the liver of all type II patients tested. Furthermore, the concentration of hPSTI protein was found to be higher in the liver of type II citrullinemia than in control. These results suggest that hPSTI may be related to the primary defect of type II citrullinemia and may be useful as a diagnostic marker, although the detailed mechanism of the high expression of hPSTI mRNA in type II liver is not yet known.

Amino Acid Metabolism, Inborn Errors↗
PubMed1987

Increased urinary excretion of argininosuccinate in type II citrullinemia.

Although argininosuccinate is a product of the catalytic action of deficient argininosuccinate synthetase in citrullinemia, its concentration was found to be elevated in the urine of patients with type II citrullinemia. Urinary argininosuccinate was identified by two methods; its conversions to anhydride by boiling in an acidic solution and to arginine by the enzymatic action of argininosuccinate lyase. Oral administration of citrulline to patients with type II citrullinemia and control subjects increased urinary argininosuccinate levels. These phenomena are consistent with our previous findings on type II citrullinemia (Adv Exp Med Biol 1983;153:63-76,J Clin Biochem Nutr 1986;1:129-142), namely that renal argininosuccinate synthetase which plays a role in arginine synthesis is not deficient in patients with type II citrullinemia; and that serum arginine levels in patients with type II citrullinemia are rather higher than the controls, and increase after the oral administration of citrulline. The organ-specific deficiency of argininosuccinate synthetase in type II citrullinemia is further confirmed by this paper.

Administration, Oral↗
PubMed1993

A search for the primary abnormality in adult-onset type II citrullinemia.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, we show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. We also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus.

Adolescent↗
PubMed2002

Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia, an autosomal recessive inherited defect of the urea cycle. Most patients described so far have presented with the classical form of the disease. There are also patients with a mild form of citrullinemia in whom the exact molecular basis and clinical relevance are uncertain. Mutations in the human ASS gene have not yet been described in mildly affected or asymptomatic patients with citrullinemia. The genomic sequence of the human ASS gene is not precisely known making mutation analysis difficult. Here, the entire genomic DNA sequence and mutations in the ASS gene of patients with the classical and mild form of the disease are described. The mutations c.1168G-->A (G390R) and IVS13+5 G-->A and the novel mutation c.323G-->T (R108L) have been found to be associated with classical citrullinemia, whereas the novel mutations c.535T-->G (W179R), and c.1085G-->T (G362V) have been detected on alleles of the mildly affected patients. Thus, mutations found in the human ASS gene of asymptomatic children with biochemical abnormalities and in some cases enzymatically proven citrullinemia have allowed us to classify these cases as ASS-deficient patients. The elucidation of the structure of the human ASS gene has made possible the use of intronic primers for molecular analysis of patients with mild disease and the classical form, and provides another option for prenatal diagnostics in affected families with the severe type.

Amino Acid Sequence↗
PubMed1993

Low incidence of citrullinemia carriers among dairy cattle of the United States.

Bovine citrullinemia is an autosomal recessive disorder that is lethal in the early postnatal period. Dairy bulls from the US were screened for citrullinemia genotype with a mutation-specific assay of semen or leukocyte DNA. One heterozygote was detected among 367 US Holstein bulls tested, corresponding to an incidence of .3%; DNA sequencing showed that this bull (bull C) was heterozygous for the translation-termination mutation described as the cause of bovine citrullinemia. Tests on daughters of bull C revealed that 26 were heterozygous and 25 were homozygous normal, confirming that the condition is autosomal recessive and that bull C was heterozygous. Although bull C was among 273 bulls tested from the top 400 bulls based on Type-Production Index as of July 1990, he was not among the 90 tested from the top 100. He has fewer than 2000 offspring registered with the Holstein Association of America and has few sons in AI. Furthermore, he was culled for other reasons before his citrullinemia status was known. Accordingly, the incidence of citrullinemia carriers is low among US Holsteins, and the impact of the one carrier found on the future of the breed is expected to be minor. No carriers were found among 102 US Guernsey bulls and 53 US Jersey bulls tested.

Animals↗
PubMed1991

Additional mutations in argininosuccinate synthetase causing citrullinemia.

Deficiency of argininosuccinate synthetase causes arginine auxotrophy in lower organisms and causes citrullinemia in humans and cattle. Previously, seven missense mutations, four mutations associated with an absence of an exon in mRNA, and one splicing mutation have been identified in human neonatal citrullinemia. Reverse transcription of mRNA, amplification of cDNA and sequencing of cDNA clones were used to identify two additional missense mutations causing citrullinemia. One mutation involves substitution of leucine for serine at position 18 (S18L) and the other a substitution of cysteine for arginine at position 86 (R86C). Both of these mutations represent C----T transitions in CpG dinucleotides, and eight of nine missense mutations causing human citrullinemia involve similar transitions in CpG dinucleotides. The nucleotide coding sequence and deduced amino acid analysis are available for four mammalian species, yeast and three bacterial species. Six of nine missense mutations in humans occur in amino acid positions that are completely conserved in these organisms. Mutations causing human citrullinemia are extremely heterogeneous, and all non-consanguineous individuals studied to date are compound heterozygotes.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Feasibility of auxiliary partial orthotopic liver transplantation from living donors for patients with adult-onset type II citrullinemia.

More than 20 patients with adult-onset type II citrullinemia have undergone liver transplantation, showing dramatic therapeutic effects. In Japan, living donor liver transplantation is the standard technique of liver transplantation because of the rare availability of cadaveric donors. The feasibility of auxiliary partial orthotopic liver transplantation (APOLT) for adult-onset type II citrullinemia to overcome the problem of a small-for-size graft in living donor liver transplantation has not been defined. We recently performed APOLT for patients with type II citrullinemia. Here, we present 2 patients: patient 1 was a 32-year-old man and patient 2 was a 43-year-old woman. Both patients suffered from hepatic encephalopathy, and laboratory data showed highly elevated plasma levels of ammonia and citrulline. In patient 1, the liver graft was obtained from a patient with familial amyloid polyneuropathy as a domino liver transplant. In patient 2, APOLT was performed after graft donation from her husband. The postoperative clinical courses of both patients were uneventful, and the neurological symptoms were completely resolved. The plasma concentrations of ammonia and citrulline normalized rapidly in both patients. APOLT can provide an adequate hepatocyte mass to correct the underlying enzyme deficiency in adult patients with type II citrullinemia. In addition, APOLT can be carried out safely to overcome the limitation of graft volume in living donor liver transplantation.

Adult↗
PubMed2006

Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine in citrullinemia.

Citrullinemia is an inborn error of the urea cycle with deficiency of the argininosuccinate synthase. It is characterized by elevated concentrations of l-citrulline and decreased levels of l-arginine in body fluids. Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthase that converts l-arginine to l-citrulline and nitric oxide (NO). Asymmetric dimethylarginine is hydrolyzed by the enzyme dimethylarginine dimethylaminohydrolase to l-citrulline and dimethylamine. Elevation of l-citrulline in citrullinemia prompted us to study the l-arginine/NO pathway in this disorder. In 8 children with citrullinemia (3 days to 3 years of age), elevated plasma levels of asymmetric dimethylarginine (P = .028) were found compared with age-matched healthy children. We hypothesize that the l-arginine/NO pathway plays a role in the pathophysiology of citrullinemia.

Arginine↗
PubMed2000

Mutation analysis of Korean patients with citrullinemia.

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.

Alleles↗
PubMed1997

Mutations and DNA diagnoses of classical citrullinemia.

Classical citrullinemia is an autosomal recessive disease caused by a genetic deficiency of argininosuccinate synthetase (ASS). We have previously identified 20 mutations in ASS mRNA of human classical citrullinemia and already established the DNA diagnosis of seven mutations as follows. By Southern blot analysis, each of the alleles with exon 5 or 6 deletion in mRNA appears to involve deletion of genomic DNA from this region. Five mutations involving R304W, G324S, IVS-6(-2) (delta Ex7), IVS-13(+5) (delta Ex13), and delta 13 bp/Ex15&IVS-15 (ins37 b/Ex15&16) are diagnosed by a combination of PCR (or modified PCR) and restriction enzyme digestion. It is important to identify the mutation in genomic DNA for prenatal diagnosis and carrier detection. In the present study, we report a novel missense mutation (R279Q) and a new abnormality in the ASS gene (delta 11 bp/IVS-15). As three missense mutations (R272C, R279Q, and G280R) were found in exon 12, we isolated and sequenced the intron regions surrounding exon 12 to establish a DNA diagnostic test. Although a mutation with a deletion of the first seven bases in exon 16 of mRNA (delta 7 b/Ex16) was found in both Japanese and American patients, the abnormality on the ASS gene was different between the Japanese allele (delta 11 bp/IVS-15) and American allele (IVS-15(-1)). The DNA diagnosis of 47 Japanese alleles with classical citrullinemia showed that the IVS-6(-2) and R304W mutations were found in 49% and 17% of the mutated alleles, respectively. We now have DNA diagnosis systems to detect 14 out of 22 mutations and are performing prenatal diagnosis and carrier detection using genomic DNA on classical citrullinemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Citrullinemia: quantitative deficiency of argininosuccinate synthetase in the liver.

Two cases of citrullinemia were reported. Case 1 was an one month old female. Her clinical course and findings were different from the fulminant type of neonatal citrullinemia reported in predominantly Caucasian countries. Our patient was well controlled under a low protein diet and essential amino acids till 9 months of age, but unfortunately she died of Reye's like syndrome. Case 2 was 31 year old male (at the time of death). He was admitted to our hospital because of hyperammonemia and mental retardation. By subsequent laboratory investigations he was diagnosed as having adult type of citrullinemia and died of hepatoma. Enzymological analysis revealed that argininosuccinate synthetase (ASS) activities in the liver tissues of the patients decreased to 40% (Case 1), 20% (Case 2) compared with those in control liver tissues. The other urea cycle enzyme activities were all within normal range. ASS activities in the kidney and brains of the two cases were within normal range. The kinetic constant values of ASS for three substrates in the tissues of liver and kidney were all normal. Results of immunochemical analyses indicated that citrullinemia in our patients was caused by a quantitative deficiency of ASS associated proteins of the liver and kidney tissues as to the molecular weight.

Adenosine Triphosphate↗
PubMed1986

Messenger RNA coding for argininosuccinate synthetase in citrullinemia.

Messenger RNA coding for argininosuccinate synthetase (ASS), extracted from the livers of some patients with citrullinemia, was analyzed using a cell-free translation system and dot and Northern blot hybridization with cDNA probe for ASS. In patients with quantitative-type citrullinemia, called type II here, previous studies have demonstrated that the hepatic content of the enzyme was about 10% of the control value, whereas the translatable mRNA level for the enzyme was similar to that of control livers. Here, we confirmed that the type II liver contained an almost normal amount of mRNA coding for ASS, judged by the dot-blot hybridization technique with cDNA. Northern blot hybridization of RNA indicated that there was hybridizable mRNA of approximately normal size (about 1.7 kilobase [kb]) in each, suggesting that large structural gene deletions had not occurred. These results indicate that in type II citrullinemia, the decrease in the enzyme protein is due either to increased degradation of the enzyme or to decreased or inhibited translation in the liver. Another type of citrullinemia was found and classified as type III. It is characterized by no detectable enzyme activity for ASS or translation activity for ASS mRNA. However, a smaller amount of RNA molecule hybridized for ASS cDNA was detected.

Adult↗
PubMed1994

Mutations in argininosuccinate synthetase mRNA of Japanese patients, causing classical citrullinemia.

Citrullinemia is an autosomal recessive disease caused by a genetic deficiency of argininosuccinate synthetase. In order to characterize mutations in Japanese patients with classical citrullinemia, RNA isolated from 10 unrelated patients was reverse-transcribed, and cDNA amplified by PCR was cloned and sequenced. The 10 mutations identified included 6 missense mutations (A118T, A192V, R272C, G280R, R304W, and R363L), 2 mutations associated with an absence of an exon 7 or exon 13, 1 mutation with a deletion of the first 7 bp in exon 16 (which might be caused by abnormal splicing), and 1 mutation with an insertion of 37 bp within exons 15 and 16 in cDNA. The insertion mutation and the five missense mutations (R304W being excluded) are new mutations described in the present paper. These are in addition to 14 mutations (9 missense mutations, 4 mutations associated with an absence of an exon in mRNA, and 1 splicing mutation) that we identified previously in mainly American patients with neonatal citrullinemia. Two of these 20 mutations, a deletion of exon 13 sequence and a 7-bp deletion in exon 16, were common to Japanese and American populations from different ethnic backgrounds; however, other mutations were unique to each population. Furthermore, the presence of a frequent mutation--the exon 7 deletion mutation in mRNA, which accounts for 10 of 23 affected alleles--was demonstrated in Japanese citrullinemia. This differs from the situation in the United States, where there was far greater heterogeneity of mutations.

Adult↗
PubMed2004

Pregnancy in a healthy woman with untreated citrullinemia.

We report the clinical and biochemical data on a second successful pregnancy in a woman with citrullinemia due to argininosuccinate synthetase deficiency (CTLN1). Despite very elevated plasma and urine citrulline and little or no measurable argininosuccinate synthetase enzyme activity on cultured skin fibroblasts, this 29-year-old woman, who was identified through newborn screening, has remained asymptomatic throughout her life. Mutation analysis has recently revealed that she is a compound heterozygote for a known and a novel mutation (IVS15-1G > C and K310Q, respectively). Many newborn screening programs have recently been expanded to include citrullinemia and numerous asymptomatic hypercitrullinemic infants and children have been identified. It is now important to define prognostic indicators that will help with treatment decisions and genetic counseling for these patients. This patient, as the only citrullinemic adult who has been followed prospectively, contributes important information in this regard. In addition, her child was unaffected by the high citrulline levels demonstrated in amniotic fluid and breast milk suggesting that citrulline is not teratogenic. Although pregnancy is an important risk factor for women with CTLN1, it appears that females with citrullinemia can have normal pregnancy outcomes, as long as metabolic crisis is avoided.

Adult↗
PubMed2006

Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro.

Citrullinemia is an inborn error of the urea cycle caused by deficient argininosuccinate synthetase, which leads to accumulation of L-citrulline and ammonia in tissues and body fluids. The main symptoms include convulsions, tremor, seizures, coma, and brain edema. The pathophysiology of the neurological signs of citrullinemia remains unclear. In this context, we investigated the in vitro effects of L-citrulline and ammonia in cerebral cortex from 30-day-old rats on oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS), chemiluminescence, mitochondrial membrane protein thiol content, intracellular content of hydrogen peroxide, total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) as well as on the activities of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). L-Citrulline significantly diminished TRAP (26%) and TAR (37%), while ammonia decreased TAR (30%). Ammonia increased SOD activity (65%) and L-citrulline did not affect the activities of any antioxidant enzymes. We also observed that L-citrulline and ammonia did not alter lipid peroxidation parameters, levels of hydrogen peroxide, and mitochondrial membrane protein thiol content. Taken together, these results may indicate that L-citrulline and ammonia decreased the antioxidant capacity of the brain, which may reflect a possible involvement of oxidative stress in the neuropathology of citrullinemia.

Ammonia↗
PubMed2006

Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma.

Citrullinemia is a metabolic disorder characterized by elevated plasma concentrations of citrulline and ammonia. Adult-onset citrullinemia (type II, CTLN2) has been attributed to citrin deficiency caused by mutations in the SLC25A13 gene. CTLN2 is associated with a high incidence of hepatocellular carcinoma (HCC) in Japanese. We report a 48-year-old Taiwanese man with citrullinemia, who was in good health until the age of 34 when he had repeated episodes of consciousness disturbance. Hyperammonia (201 micromol/L) was found during an episode of coma. Liver function and electrolyte levels were normal at that time. Serologic markers of viral hepatitis B and C were negative. Analysis of genomic DNA extracted from peripheral blood leukocytes showed homozygous 851del4 mutation in exon 9 of the SLC25A13 gene on chromosome 7q21.3. Fourteen years after disease onset, at the age of 48, he was admitted due to an episode of coma. Abdominal sonography and computed tomography showed a 2.5 cm tumor in the left lobe of the liver, without evidence of liver cirrhosis. Wedge resection of the tumor was performed and grade 2 HCC was diagnosed. The nontumor part of the resected specimen showed chronic persistent hepatitis with moderate steatosis. The results in this case support that both citrin deficiency and steatohepatitis may contribute to hepatocarcinogenesis.

Biopsy, Fine-Needle↗