Citrullinemia
Argininosuccinate Synthase
Citrulline
Amino Acid Metabolism, Inborn Errors
Sodium Benzoate
Hyperammonemia
Trypsin Inhibitor, Kazal Pancreatic
Thyroxine-Binding Globulin
Ammonia
Mitochondrial Membrane Transport Proteins
Type II citrullinemia in an elderly patient treated with living related partial liver transplantation. (1/41)
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. (2/41)
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. (3/41)
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. (4/41)
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. (5/41)
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. (6/41)
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. (7/41)
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. (8/41)
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)Citrullinemia is a rare inherited metabolic disorder characterized by the body's inability to properly process and eliminate certain toxic byproducts that are generated during the breakdown of proteins. This condition results from a deficiency of the enzyme argininosuccinate synthetase, which is required for the normal functioning of the urea cycle. The urea cycle is a series of biochemical reactions that occur in the liver and help to convert ammonia, a toxic substance, into urea, which can then be excreted by the kidneys.
There are two main types of citrullinemia: type I (also known as classic citrullinemia) and type II (also known as citrullinemia type II or adult-onset citrullinemia). Type I is typically more severe and can present in newborns with symptoms such as poor feeding, vomiting, seizures, and developmental delays. If left untreated, it can lead to serious complications, including intellectual disability, coma, and even death.
Type II citrullinemia, on the other hand, tends to present later in life, often in adulthood, and may cause symptoms such as confusion, seizures, and neurological problems. It is important to note that some individuals with type II citrullinemia may never develop any symptoms at all.
Treatment for citrullinemia typically involves a combination of dietary restrictions, supplements, and medications to help manage the buildup of toxic byproducts in the body. In severe cases, liver transplantation may be considered as a last resort.
Argininosuccinate synthase (ASS) is a urea cycle enzyme that plays a crucial role in the detoxification of ammonia in the body. This enzyme catalyzes the reaction that combines citrulline and aspartate to form argininosuccinate, which is subsequently converted to arginine and fumarate in the urea cycle.
The reaction catalyzed by argininosuccinate synthase is as follows:
Citrulline + Aspartate + ATP → Argininosuccinate + AMP + PPi
Deficiency in argininosuccinate synthase leads to a genetic disorder known as citrullinemia, which is characterized by an accumulation of ammonia in the blood and neurodevelopmental abnormalities. There are two forms of citrullinemia, type I and type II, with type I being more severe and caused by mutations in the ASS1 gene located on chromosome 9q34.
L-Citrulline is a non-essential amino acid that plays a role in the urea cycle, which is the process by which the body eliminates toxic ammonia from the bloodstream. It is called "non-essential" because it can be synthesized by the body from other compounds, such as L-Ornithine and carbamoyl phosphate.
Citrulline is found in some foods, including watermelon, bitter melon, and certain types of sausage. It is also available as a dietary supplement. In the body, citrulline is converted to another amino acid called L-Arginine, which is involved in the production of nitric oxide, a molecule that helps dilate blood vessels and improve blood flow.
Citrulline has been studied for its potential benefits on various aspects of health, including exercise performance, cardiovascular function, and immune system function. However, more research is needed to confirm these potential benefits and establish safe and effective dosages.
Inborn errors of amino acid metabolism refer to genetic disorders that affect the body's ability to properly break down and process individual amino acids, which are the building blocks of proteins. These disorders can result in an accumulation of toxic levels of certain amino acids or their byproducts in the body, leading to a variety of symptoms and health complications.
There are many different types of inborn errors of amino acid metabolism, each affecting a specific amino acid or group of amino acids. Some examples include:
* Phenylketonuria (PKU): This disorder affects the breakdown of the amino acid phenylalanine, leading to its accumulation in the body and causing brain damage if left untreated.
* Maple syrup urine disease: This disorder affects the breakdown of the branched-chain amino acids leucine, isoleucine, and valine, leading to their accumulation in the body and causing neurological problems.
* Homocystinuria: This disorder affects the breakdown of the amino acid methionine, leading to its accumulation in the body and causing a range of symptoms including developmental delay, intellectual disability, and cardiovascular problems.
Treatment for inborn errors of amino acid metabolism typically involves dietary restrictions or supplementation to manage the levels of affected amino acids in the body. In some cases, medication or other therapies may also be necessary. Early diagnosis and treatment can help prevent or minimize the severity of symptoms and health complications associated with these disorders.
Sodium benzoate is a chemical compound with the formula NaC7H5O2. It is a white crystalline powder that is readily soluble in water and alcohol. Sodium benzoate is a preservative commonly added to foods, beverages, and pharmaceuticals to inhibit microbial growth.
In medical terms, sodium benzoate may also be used as a medication to treat certain metabolic disorders such as hyperammonemia, which can occur in conditions like urea cycle disorders or liver disease. In these cases, sodium benzoate acts by binding with excess ammonia in the body and converting it into a compound that can be excreted through the kidneys.
It is important to note that people with a rare genetic disorder called benzoic aciduria should avoid foods or medications containing sodium benzoate, as they are unable to metabolize this compound properly.
Hyperammonemia is a medical condition characterized by an excessively high level of ammonia (a toxic byproduct of protein metabolism) in the blood. This can lead to serious neurological symptoms and complications, as ammonia is highly toxic to the brain. Hyperammonemia can be caused by various underlying conditions, including liver disease, genetic disorders that affect ammonia metabolism, certain medications, and infections. It is important to diagnose and treat hyperammonemia promptly to prevent long-term neurological damage or even death. Treatment typically involves addressing the underlying cause of the condition, as well as providing supportive care such as administering medications that help remove ammonia from the blood.
Trypsin Inhibitor, Kazal Pancreatic is a type of protein that is produced in the pancreas and functions as an inhibitor to trypsin, which is a proteolytic enzyme involved in digestion. Specifically, this inhibitor belongs to the Kazal-type serine protease inhibitors. It helps regulate the activity of trypsin within the pancreas, preventing premature activation and potential damage to pancreatic tissue. Any imbalance or deficiency in this inhibitor can lead to pancreatic diseases such as pancreatitis.
Thyroxine-binding globulin (TBG) is a glycoprotein found in human plasma that has a high affinity for binding thyroid hormones, specifically Thyroxine (T4) and Triiodothyronine (T3). It is produced by the liver and plays a crucial role in maintaining the balance of these hormones in the body. TBG binds to approximately 70-80% of circulating T4 and about 55% of circulating T3, acting as a transport protein that carries these hormones throughout the body. The amount of TBG in the blood can vary due to factors such as genetics, sex hormones, and certain medications, which can affect the levels of free (unbound) thyroid hormones and contribute to various thyroid-related disorders.
Ammonia is a colorless, pungent-smelling gas with the chemical formula NH3. It is a compound of nitrogen and hydrogen and is a basic compound, meaning it has a pH greater than 7. Ammonia is naturally found in the environment and is produced by the breakdown of organic matter, such as animal waste and decomposing plants. In the medical field, ammonia is most commonly discussed in relation to its role in human metabolism and its potential toxicity.
In the body, ammonia is produced as a byproduct of protein metabolism and is typically converted to urea in the liver and excreted in the urine. However, if the liver is not functioning properly or if there is an excess of protein in the diet, ammonia can accumulate in the blood and cause a condition called hyperammonemia. Hyperammonemia can lead to serious neurological symptoms, such as confusion, seizures, and coma, and is treated by lowering the level of ammonia in the blood through medications, dietary changes, and dialysis.
Mitochondrial membrane transport proteins are a type of integral membrane proteins located in the inner and outer mitochondrial membranes. They play a crucial role in the regulation of molecule exchange between the cytosol and the mitochondrial matrix, allowing only specific ions and molecules to pass through while maintaining the structural and functional integrity of the mitochondria.
The inner mitochondrial membrane transport proteins, also known as the mitochondrial carrier proteins or the solute carriers, are a family of about 50 different types of proteins that facilitate the passage of various metabolites, such as nucleotides, amino acids, fatty acids, and inorganic ions (like calcium, sodium, and potassium). These transport proteins usually function as exchangers or uniporters, moving one type of solute in one direction in exchange for another type of solute or a proton.
The outer mitochondrial membrane is more permeable than the inner membrane due to the presence of voltage-dependent anion channels (VDACs) and other porins that allow small molecules, ions, and metabolites to pass through. VDACs are the most abundant proteins in the outer mitochondrial membrane and play a significant role in controlling the flow of metabolites between the cytosol and the intermembrane space.
In summary, mitochondrial membrane transport proteins are essential for maintaining the proper functioning of mitochondria by regulating the movement of molecules across the inner and outer membranes. They facilitate the exchange of nutrients, metabolites, and ions required for oxidative phosphorylation, energy production, and other cellular processes.
Ligases are a group of enzymes that catalyze the formation of a covalent bond between two molecules, usually involving the joining of two nucleotides in a DNA or RNA strand. They play a crucial role in various biological processes such as DNA replication, repair, and recombination. In DNA ligases, the enzyme seals nicks or breaks in the phosphodiester backbone of the DNA molecule by catalyzing the formation of an ester bond between the 3'-hydroxyl group and the 5'-phosphate group of adjacent nucleotides. This process is essential for maintaining genomic integrity and stability.