Ornithine Carbamoyltransferase Deficiency Disease
Ornithine Carbamoyltransferase
Mannosidase Deficiency Diseases
Carbamoyl-Phosphate Synthase I Deficiency Disease
Aspartate Carbamoyltransferase
Carbamyl Phosphate
Immunologic Deficiency Syndromes
Multiple Sulfatase Deficiency Disease
Citrulline
Carboxyl and Carbamoyl Transferases
Ornithine Decarboxylase
Optimization of allopurinol challenge: sample purification, protein intake control, and the use of orotidine response as a discriminative variable improve performance of the test for diagnosing ornithine carbamoyltransferase deficiency. (1/85)
BACKGROUND: The diagnosis of heterozygosity for X-linked ornithine carbamoyltransferase (OCT) deficiency has usually been based on measurement of the increase of orotate and orotidine excretion after an allopurinol load. We examined the choices of analyte, cutoff, and test conditions to obtain maximal test accuracy. METHODS: Urine orotate/orotidine responses to allopurinol load in 37 children (13 OCT-deficient and 24 non-OCT-deficient) and 24 women (7 at risk for carrier status and 17 not related to OCT-deficient children) were analyzed by liquid chromatography after sample purification by anion-exchange chromatography. Diagnostic accuracy was evaluated by nonparametric ROC curves. RESULTS: Sample purification was necessary to prevent interferences. Orotate and orotidine excretion increased with increased protein intake during the test. At a cutoff of 8 mmol orotidine/mol creatinine, sensitivity was 1.0 and specificity was 0. 92 in mild forms of OCT deficiency. Results in monoplex carrier women may differ greatly from those expected because of the genetics of this deficiency. CONCLUSIONS: Standardization of protein intake is required in the allopurinol loading test. A negative response in the face of clinical suspicion should be followed with a repeat test during a protein intake not <2.5 g x kg-1 x day-1. Measurements of orotidine provide better clinical sensitivity than measurements of orotate. (+info)Efficient mitochondrial import of newly synthesized ornithine transcarbamylase (OTC) and correction of secondary metabolic alterations in spf(ash) mice following gene therapy of OTC deficiency. (2/85)
BACKGROUND: The mouse strain sparse fur with abnormal skin and hair (spf(ash)) is a model for the human ornithine transcarbamylase (OTC) deficiency, an X-linked inherited urea cycle disorder. The spf(ash) mouse carries a single base-pair mutation in the OTC gene that leads to the production of OTC enzyme at 10% of the normal level. MATERIALS AND METHODS: Recombinant adenoviruses carrying either mouse (Ad.mOTC) or human (Ad.hOTC) OTC cDNA were injected intravenously into the spf(ash) mice. Expression of OTC enzyme precursor and its translocation to mitochondria in the vector-transduced hepatocytes were analyzed on an ultrastructural level. Liver OTC activity and mitochondrial OTC concentration were significantly increased (300% of normal) in mice treated with Ad.mOTC and were moderately increased in mice receiving Ad.hOTC (34% of normal). The concentration and subcellular location of OTC and associated enzymes were studied by electron microscope immunolocalization and quantitative morphometry. RESULTS: Cytosolic OTC concentration remained unchanged in Ad.mOTC-injected mice but was significantly increased in mice receiving Ad.hOTC, suggesting a block of mitochondria translocation for the human OTC precursor. Mitochondrial ATPase subunit c [ATPase(c)] was significantly reduced and mitochondrial carbamy delta phosphate synthetase I (CPSI) was significantly elevated in spf(ash) mice relative to C3H. In Ad.mOTC-treated mice, the hepatic mitochondrial concentration of ATPase(c) was completely normalized and the CPSI concentration was partially corrected. CONCLUSIONS: Taken together, we conclude that newly synthesized mouse OTC enzyme was efficiently imported into mitochondria following vector-mediated gene delivery in spf(ash) mice, correcting secondary metabolic alterations. (+info)Aberrations of ammonia metabolism in ornithine carbamoyltransferase-deficient spf-ash mice and their prevention by treatment with urea cycle intermediate amino acids and an ornithine aminotransferase inactivator. (3/85)
Sparse fur with abnormal skin and hair (spf-ash) mice are deficient in ornithine carbamoyltransferase (OCT) activity, but their OCT protein is kinetically normal. We administered ammonium chloride to spf-ash mice, in order to analyze ammonia metabolism and to find a rationale for the therapy of OCT deficiency. Ammonia concentration in the liver of spf-ash mice increased to a level much higher than in the control. Ammonium chloride injection caused an increase in ornithine (Orn) 5 min after injection and an increase in the sum of Orn, citrulline (Cit) and arginine (Arg) for at least 15 min in the liver of control mice, but no increase in Orn, Cit and Arg in the liver of spf-ash mice. Treatment of spf-ash mice with Arg 5-20 min prior to the injection of ammonium chloride kept the hepatic ammonia concentration at a level comparable to that without the load. A significant reciprocal relationship between ammonia and Orn concentrations in the liver of spf-ash mice 5 min after an ammonium chloride load with or without Arg strongly suggests that ammonia disposal is dependent on the supply of Orn. In spf-ash mice loaded with tryptone as a nitrogen source, Arg supplementation showed a dramatic decrease in urinary orotic acid excretion in a dose-dependent manner. Similar effects were observed with Cit and Orn at the same dose, and a long-lasting effect with an ornithine aminotransferase inactivator, 5-(fluoromethyl)ornithine, at a much lower dose. The rate of urea formation in liver perfused with ammonium chloride was lower in spf-ash mice than in controls, but with the addition of Orn to the medium it increased to a similar level in control and spf-ash mice. These results indicate that OCT is not saturated with Orn in vivo under physiological conditions and that the administration or enrichment of the urea cycle intermediate amino acids enhances the OCT reaction so that the ammonia metabolism of OCT-deficient spf-ash mice is at least partially normalized. (+info)Under recognition of late onset ornithine transcarbamylase deficiency. (4/85)
Late onset ornithine transcarbamylase deficiency (McKusick 311250) is reported in four Finnish patients, two boys and two heterozygous girls. The subtle onset and course of ornithine transcarbamylase deficiency emphasises the need for plasma ammonia and amino acid measurements in clinical situations suggesting a disorder of this nature. (+info)Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus. (5/85)
A 57 year old woman with post-traumatic complex partial seizures was admitted because of recurrent episodes of altered mental state over the preceding 4 years, each lasting up to 5 days. There was a history of dietary protein intolerance since childhood and two of her daughters had died in the neonatal period from unexplained encephalopathies. In hospital she developed fluctuating confusion, amnesia, and sudden episodes of unresponsiveness. An EEG was consistent with complex partial status epilepticus but there was no response to benzodiazepines. Nasogastric feeding and sodium valproate were given and shortly afterwards she lapsed into a deep coma. Blood ammonia and urinary orotate were raised, and genetic testing confirmed that she was a carrier of a mutation in exon 3 of the ornithine transcarbamylase gene (C to T at position 92). Treatment with protein restriction, carnitine, and sodium phenylbutyrate led to a full recovery over a period of 3 months. To our knowledge this is the oldest age of onset yet described in a manifesting carrier. She is the fifth patient with heterozygous ornithine transcarbamylase deficiency reported to have had a severe reaction to sodium valproate. Hyperammonaemic encephalopathy should be considered in patients of any age who experience fluctuating confusion. (+info)Transient depletion of CD4 lymphocyte improves efficacy of repeated administration of recombinant adenovirus in the ornithine transcarbamylase deficient sparse fur mouse. (6/85)
One of the current limitations of adenoviral gene therapy is a vector-induced humoral immune response that blocks effective re-administration of the vector. In an animal model of the inborn error of urea synthesis ornithine transcarbamylase (OTC) deficiency, the sparse fur (spf/y) mouse, we tested a strategy to transiently block the CD4 mediated immune response at the time of virus administration using an anti-CD4 monoclonal antibody (GK1.5). The co-administration of GK1.5 resulted in a significantly diminished production of neutralizing antibody to the adenovirus vector, but minimally prolonged metabolic correction. A second infusion of the same virus in GK1.5 treated spf/y mice led to a complete normalization of liver OTC activity at day 3 after infection and a significant metabolic correction of urinary orotate and plasma glutamine. In contrast, there was no evidence of enhanced OTC expression or metabolic correction (measured by normalization of plasma glutamine and urinary orotate) after the second infusion of virus in spf/y mice not treated with GK1.5. Furthermore, when co-administered with two consecutive doses of adenovirus, the anti-CD4 treatment allowed improved transgene expression upon a third administration of virus and a partial normalization of the metabolic abnormalities, compared with mice that did not receive anti-CD4 treatment. The level of OTC expression from the third viral infusion, however, was lower than that from the second viral infusion. Passive transfer experiments suggest that low levels of neutralizing antibodies developing over repeated viral administration was the likely cause of the reduced transgene expression. Together, these findings demonstrated that the host immune system can be modulated to permit effective transgene expression at therapeutic levels by re-administered adenoviral vectors. (+info)Localized proton MR spectroscopy in infants with urea cycle defect. (7/85)
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)Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. (8/85)
The clinical syndrome of encephalopathy is most often encountered in the context of decompensated liver disease and the diagnosis is usually clear cut. Non-hepatic causes of encephalopathy are rarer and tend to present to a wide range of medical specialties with variable and episodic symptoms. Delay can result in the development of potentially life threatening complications, such as seizures and coma. Early recognition is vital. A history of similar episodes or clinical risk factors and early assessment of blood ammonia levels help establish the diagnosis. In addition to adequate supportive care, investigation of the underlying cause of the hyperammonaemia is essential and its reversal, where possible, will often result in complete recovery. Detection of an unborn error of metabolism should lead to the initiation of appropriate maintenance therapy and genetic counselling. (+info)Ornithine Carbamoyltransferase (OCT) Deficiency Disease, also known as Ornithine Transcarbamylase Deficiency, is a rare inherited urea cycle disorder. It is caused by a deficiency of the enzyme ornithine carbamoyltransferase, which is responsible for one of the steps in the urea cycle that helps to rid the body of excess nitrogen (in the form of ammonia).
When OCT function is impaired, nitrogen accumulates and forms ammonia, leading to hyperammonemia (elevated blood ammonia levels), which can cause neurological symptoms such as lethargy, vomiting, irritability, and in severe cases, coma or death.
Symptoms of OCT deficiency can range from mild to severe and may include developmental delay, seizures, behavioral changes, and movement disorders. The diagnosis is typically made through newborn screening tests, enzyme assays, and genetic testing. Treatment usually involves a combination of dietary restrictions, medications that help remove nitrogen from the body, and in some cases, liver transplantation.
Ornithine carbamoyltransferase (OCT or OAT) is an enzyme that plays a crucial role in the urea cycle, which is the biochemical pathway responsible for the removal of excess nitrogen from the body. Specifically, ornithine carbamoyltransferase catalyzes the transfer of a carbamoyl group from carbamoyl phosphate to ornithine, forming citrulline and releasing phosphate in the process. This reaction is essential for the production of urea, which can then be excreted by the kidneys.
Deficiency in ornithine carbamoyltransferase can lead to a genetic disorder called ornithine transcarbamylase deficiency (OTCD), which is characterized by hyperammonemia (elevated blood ammonia levels) and neurological symptoms. OTCD is one of the most common urea cycle disorders, and it primarily affects females due to its X-linked inheritance pattern.
Mannosidosis is a rare inherited metabolic disorder caused by a deficiency of the enzyme alpha-mannosidase, which is responsible for breaking down complex sugar molecules called mannose-rich oligosaccharides. When the enzyme is not functioning properly, these sugar molecules accumulate in various tissues and organs, leading to progressive damage.
There are two main types of Mannosidosis: type I (also known as classic Mannosidosis) and type II (also known as mild or attenuated Mannosidosis). The symptoms and severity of the disease can vary widely between individuals and between the two types, but may include developmental delays, intellectual disability, coarse facial features, skeletal abnormalities, hearing loss, recurrent respiratory infections, and vision problems.
The diagnosis of Mannosidosis is typically made through enzyme assay and genetic testing. Treatment is primarily supportive and may include physical therapy, speech therapy, hearing aids, and management of respiratory and other medical issues as they arise. In some cases, bone marrow transplantation may be considered as a treatment option.
Ornithine is not a medical condition but a naturally occurring alpha-amino acid, which is involved in the urea cycle, a process that eliminates ammonia from the body. Here's a brief medical/biochemical definition of Ornithine:
Ornithine (NH₂-CH₂-CH₂-CH(NH₃)-COOH) is an α-amino acid without a carbon atom attached to the amino group, classified as a non-proteinogenic amino acid because it is not encoded by the standard genetic code and not commonly found in proteins. It plays a crucial role in the urea cycle, where it helps convert harmful ammonia into urea, which can then be excreted by the body through urine. Ornithine is produced from the breakdown of arginine, another amino acid, via the enzyme arginase. In some medical and nutritional contexts, ornithine supplementation may be recommended to support liver function, wound healing, or muscle growth, but its effectiveness for these uses remains a subject of ongoing research and debate.
Carbamoyl-phosphate synthase I (CPS1) deficiency disease is a rare inherited disorder of urea synthesis, which can lead to hyperammonemia (elevated blood ammonia levels) and life-threatening neurological symptoms. CPS1 is an enzyme that plays a crucial role in the first step of the urea cycle, where it catalyzes the conversion of ammonia and bicarbonate into carbamoyl phosphate.
In CPS1 deficiency disease, mutations in the CPS1 gene lead to reduced or absent enzyme activity, impairing the body's ability to detoxify ammonia. As a result, toxic levels of ammonia accumulate in the blood and can cause irreversible brain damage, intellectual disability, coma, or even death if not treated promptly and effectively.
Symptoms of CPS1 deficiency disease may include poor feeding, vomiting, lethargy, hypotonia (low muscle tone), seizures, and developmental delays. The severity of the disorder can vary widely, from a severe neonatal-onset form with early symptoms appearing within the first few days of life to a milder late-onset form that may not become apparent until later in infancy or childhood.
Treatment typically involves a combination of dietary restrictions, medications to lower ammonia levels and support liver function, and, in some cases, liver transplantation. Early diagnosis and intervention are critical for improving outcomes and minimizing the risk of long-term neurological complications.
Aspartate carbamoyltransferase (ACT) is a crucial enzyme in the urea cycle, which is the biochemical pathway responsible for the elimination of excess nitrogen waste from the body. This enzyme catalyzes the second step of the urea cycle, where it facilitates the transfer of a carbamoyl group from carbamoyl phosphate to aspartic acid, forming N-acetylglutamic semialdehyde and releasing phosphate in the process.
The reaction catalyzed by aspartate carbamoyltransferase is as follows:
Carbamoyl phosphate + L-aspartate → N-acetylglutamic semialdehyde + P\_i + CO\_2
This enzyme plays a critical role in maintaining nitrogen balance and preventing the accumulation of toxic levels of ammonia in the body. Deficiencies or mutations in aspartate carbamoyltransferase can lead to serious metabolic disorders, such as citrullinemia and hyperammonemia, which can have severe neurological consequences if left untreated.
Carbamyl Phosphate is a chemical compound that plays a crucial role in the biochemical process of nitrogen metabolism, particularly in the urea cycle. It is synthesized in the liver and serves as an important intermediate in the conversion of ammonia to urea, which is then excreted by the kidneys.
In medical terms, Carbamyl Phosphate Synthetase I (CPS I) deficiency is a rare genetic disorder that affects the production of Carbamyl Phosphate. This deficiency can lead to hyperammonemia, which is an excess of ammonia in the bloodstream, and can cause severe neurological symptoms and brain damage if left untreated.
It's important to note that while Carbamyl Phosphate is a critical component of the urea cycle, it is not typically used as a medication or therapeutic agent in clinical practice.
Immunologic deficiency syndromes refer to a group of disorders characterized by defective functioning of the immune system, leading to increased susceptibility to infections and malignancies. These deficiencies can be primary (genetic or congenital) or secondary (acquired due to environmental factors, medications, or diseases).
Primary immunodeficiency syndromes (PIDS) are caused by inherited genetic mutations that affect the development and function of immune cells, such as T cells, B cells, and phagocytes. Examples include severe combined immunodeficiency (SCID), common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, and X-linked agammaglobulinemia.
Secondary immunodeficiency syndromes can result from various factors, including:
1. HIV/AIDS: Human Immunodeficiency Virus infection leads to the depletion of CD4+ T cells, causing profound immune dysfunction and increased vulnerability to opportunistic infections and malignancies.
2. Medications: Certain medications, such as chemotherapy, immunosuppressive drugs, and long-term corticosteroid use, can impair immune function and increase infection risk.
3. Malnutrition: Deficiencies in essential nutrients like protein, vitamins, and minerals can weaken the immune system and make individuals more susceptible to infections.
4. Aging: The immune system naturally declines with age, leading to an increased incidence of infections and poorer vaccine responses in older adults.
5. Other medical conditions: Chronic diseases such as diabetes, cancer, and chronic kidney or liver disease can also compromise the immune system and contribute to immunodeficiency syndromes.
Immunologic deficiency syndromes require appropriate diagnosis and management strategies, which may include antimicrobial therapy, immunoglobulin replacement, hematopoietic stem cell transplantation, or targeted treatments for the underlying cause.
Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disorder that affects multiple organ systems in the body. It is caused by mutations in the SUMF1 gene, which provides instructions for making an enzyme called formylglycine-generating enzyme (FGE). FGE is essential for the function of several sulfatase enzymes, which are responsible for removing sulfate groups from certain sugar molecules attached to proteins and lipids.
In MSD, the activity of all or most of these sulfatase enzymes is reduced or absent, leading to the accumulation of sulfated molecules in various tissues and organs. This can result in a wide range of symptoms that typically appear in infancy or early childhood, including developmental delay, intellectual disability, coarse facial features, skeletal abnormalities, vision and hearing loss, and problems with mobility and coordination.
MSD is an autosomal recessive disorder, which means that an individual must inherit two copies of the mutated gene (one from each parent) in order to develop the disease. The incidence of MSD is estimated to be less than 1 in 1 million people worldwide. Currently, there is no cure for MSD and treatment is focused on managing symptoms and improving quality of life.
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.
Carboxyl transferases and carbamoyl transferases are two types of enzymes that play a crucial role in various metabolic pathways by transferring a carboxyl or carbamoyl group from one molecule to another. Here are the medical definitions for both:
1. Carboxyl Transferases: These are a class of enzymes that catalyze the transfer of a carboxyl group (-COOH) from one molecule to another. They play an essential role in several metabolic processes, such as the synthesis and degradation of amino acids, carbohydrates, lipids, and other biomolecules. One example of a carboxyl transferase is pyruvate carboxylase, which catalyzes the addition of a carboxyl group to pyruvate, forming oxaloacetate in the gluconeogenesis pathway.
2. Carbamoyl Transferases: These are enzymes that facilitate the transfer of a carbamoyl group (-CONH2) from one molecule to another. They participate in various metabolic reactions, including the synthesis of essential compounds like arginine, pyrimidines, and urea. An example of a carbamoyl transferase is ornithine carbamoyltransferase (OCT), which catalyzes the transfer of a carbamoyl group from carbamoyl phosphate to ornithine during the urea cycle.
Both carboxyl and carbamoyl transferases are vital for maintaining proper cellular function and homeostasis in living organisms, including humans. Dysregulation or deficiency of these enzymes can lead to various metabolic disorders and diseases.
Ornithine decarboxylase (ODC) is a medical/biochemical term that refers to an enzyme (EC 4.1.1.17) involved in the metabolism of amino acids, particularly ornithine. This enzyme catalyzes the decarboxylation of ornithine to form putrescine, which is a precursor for the synthesis of polyamines, such as spermidine and spermine. Polyamines play crucial roles in various cellular processes, including cell growth, differentiation, and gene expression.
Ornithine decarboxylase is a rate-limiting enzyme in polyamine biosynthesis, meaning that its activity regulates the overall production of these molecules. The regulation of ODC activity is tightly controlled at multiple levels, including transcription, translation, and post-translational modifications. Dysregulation of ODC activity has been implicated in several pathological conditions, such as cancer, neurodegenerative disorders, and inflammatory diseases.
Inhibitors of ornithine decarboxylase have been explored as potential therapeutic agents for various diseases, including cancer, due to their ability to suppress polyamine synthesis and cell proliferation. However, the use of ODC inhibitors in clinical settings has faced challenges related to toxicity and limited efficacy.