Pyruvate Dehydrogenase Complex Deficiency Disease
Pyruvate Dehydrogenase (Lipoamide)
Pyruvate Dehydrogenase Complex
Mannosidase Deficiency Diseases
Dihydrolipoyllysine-Residue Acetyltransferase
Ketoglutarate Dehydrogenase Complex
Dihydrolipoamide Dehydrogenase
Carbamoyl-Phosphate Synthase I Deficiency Disease
Pyruvate Dehydrogenase (Lipoamide)-Phosphatase
Immunologic Deficiency Syndromes
Thiamine Pyrophosphate
Thioctic Acid
Multiple Sulfatase Deficiency Disease
Pyruvic Acid
Pyruvates
Dichloroacetic Acid
Multiple presentation of mitochondrial disorders. (1/42)
The aim of this study was to assess the heterogeneous clinical presentations of children with mitochondrial disorders evaluated at a metabolic neurogenetic clinic. The charts of 36 children with highly suspected mitochondrial disorders were reviewed. Thirty one children were diagnosed as having a mitochondrial disorder, based on a suggestive clinical presentation and at least one of the accepted laboratory criteria; however, in five children with no laboratory criteria the diagnosis remained probable. All of the patients had nervous system involvement. Twenty seven patients also had dysfunction of other systems: sensory organs in 15 patients, cardiovascular system in five, gastrointestinal system in 20, urinary system in four, haematopoietic system in four, and endocrine system in nine. The clinical presentation was compatible with an established syndrome in only 15 children. Severe lactic acidosis or ragged red muscle fibres were encountered in very few patients. These results suggest that mitochondrial disorders should be evaluated in children presenting with a complex neurological picture or multisystem involvement. (+info)Sequential deletion of C-terminal amino acids of the E(1)alpha component of the pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of functional E(1)alpha(2)beta(2) tetramers: implications for patients with PDH deficiency. (2/42)
Human pyruvate dehydrogenase (PDH) complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. We have characterized novel mutations that affect the C-terminal portion of the PDH-E(1)alpha-coding sequence. Although the molecular defects underlying these mutations are different, both effectively produce a stop codon prematurely three amino acids from the C-terminus. The clinical and biochemical consequences of these mutations are unusual in that the affected individuals are very long-term survivors with PDH complex deficiency despite having low (<20%) activity in skin fibroblasts. These findings prompted us to investigate the C-terminus of E(1)alpha in greater detail. We constructed and expressed a series of PDH-E(1)alpha deletion mutants in a cell line with zero PDH complex activity due to a null E(1)alpha allele. Sequential deletion of the C-terminus by one, two, three and four amino acids resulted in PDH complex activities of 100, 60, 36 and 14%, respectively, compared with wild-type E(1)alpha expressed in PDH complex-deficient cells. The immunodetectable protein was decreased by the same amount as the activity, suggesting that the stability and/or assembly of the E(1)alpha(2)beta(2)heterotetramer might depend on the intactness of the PDH-E(1)alpha C-terminus. In addition, we compared the somatic and the testis-specific isoforms of E(1)alphaand concluded that they are biochemically equivalent. (+info)A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. (3/42)
The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production. (+info)Characterization of a missense mutation at histidine-44 in a pyruvate dehydrogenase-deficient patient. (4/42)
Genetic defects in pyruvate dehydrogenase complex (PDC) cause lactic acidosis, neurological deficits, and often early death. Most mutations of PDC are localized in the alpha subunit of the pyruvate dehydrogenase (E1) component. We have kinetically characterized a patient's missense mutation alphaH44R in E1alpha by creating and purifying three recombinant human E1s (alphaH44R, alphaH44Q, and alphaH44A). Substitutions at histidine-15 resulted in decreased V(max) values (6% alphaH44R; 30% alphaH44Q; 90% alphaH44A) while increasing K(m) values for thiamine pyrophosphate (TPP) compared to wild-type (alphaH44R, 3-fold; alphaH44Q, 7-fold; alphaH44A, 10-fold). This suggests that the volume of the residue at site 15 is important for TPP binding and substitution by a residue with a longer side chain disrupts the active site more than the TPP binding site. The rates of phosphorylation and dephosphorylation of alphaH44R E1 by E1-kinase and phospho-E1 phosphatase, respectively, were similar to that of the wild-type E1 protein. These results provide a biochemical basis for altered E1 function in the alphaH44R E1 patient. (+info)Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. (5/42)
The human pyruvate dehydrogenase complex (PDHC) catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine treatment is very effective for some patients with PDHC deficiency. Among these patients, five mutations of the pyruvate dehydrogenase (E1)alpha subunit have been reported previously: H44R, R88S, G89S, R263G, and V389fs. All five mutations are in a region outside the thiamine pyrophosphate (TPP)-binding region of the E1alpha subunit. We report the biochemical and molecular analysis of two patients with clinically thiamine-responsive lactic acidemia. The PDHC activity was assayed using two different concentrations of TPP. These two patients displayed very low PDHC activity in the presence of a low (1 x 10(-4) mM) TPP concentration, but their PDHC activity significantly increased at a high (0.4 mM) TPP concentration. Therefore, the PDHC deficiency in these two patients was due to a decreased affinity of PDHC for TPP. Treatment of both patients with thiamine resulted in a reduction in the serum lactate concentration and clinical improvement, suggesting that these two patients have a thiamine-responsive PDHC deficiency. The DNA sequence of these two male patients' X-linked E1alpha subunit revealed a point mutation (F205L and L216F) within the TPP-binding region in exon 7. (+info)In vivo pyruvate detected by MR spectroscopy in neonatal pyruvate dehydrogenase deficiency. (6/42)
We present a unique finding of an elevated level of pyruvate at 2.37 ppm revealed by in vivo MR spectroscopy of a female neonate. Low fibroblast pyruvate dehydrogenase (PDH) complex activity subsequently confirmed a diagnosis of PDH deficiency. Abnormalities of brain development consistent with PDH deficiency were also evident on fetal and postnatal MR images. To our knowledge, this is the first report of pyruvate being shown in vivo in a child and the first report of MR spectroscopy aiding in the diagnosis of inborn error in pyruvate metabolism before confirmation by conventional enzymatic testing. This finding has potential implications for earlier diagnosis in patients with defects in mitochondrial metabolism. (+info)Optimized spectrophotometric assay for the completely activated pyruvate dehydrogenase complex in fibroblasts. (7/42)
BACKGROUND: Analysis of the pyruvate dehydrogenase complex (PDHc) activity in human skin fibroblasts is hampered by low enzyme activity in the cells. The most commonly used radiochemical method detects the formation of (14)CO(2), an endproduct of the E1 component of PDHc, from [1-(14)C]pyruvate. METHODS: We report a spectrophotometric method for the analysis of PDHc activity in fibroblasts based on detection of NADH formation via a p-iodonitrotetrazolium violet (INT)-coupled system. We investigated in detail the specific requirements of this assay, such as cofactor requirements and the effects of suggested stimulatory compounds and different cell disruption procedures. The reliability of the optimized assay was studied by investigation of patients previously diagnosed with PDHc deficiency and by comparison with results from the radiochemical method. RESULTS: Mean (SD) total PDHc activities were 136 (31) and 58 (21) mU/U of citrate synthase in fibroblast homogenates from 10 healthy volunteers and 7 PDHc-deficient patients, respectively, by the spectrophotometric assay. Similar results were obtained in a mitochondrial fraction. Dithiothreitol (DTT) increased the nonspecific inhibitor-insensitive rate with less pronounced effect on the specific rate of PDHc activity. Administration of DTT increased PDHc activity to 193 (3)% of control activity (without DTT), but decreased the inhibitor-sensitive rate from 99 (0.3)% (without DTT) to 69 (2)% (with 0.3 mmol/L DTT). CONCLUSION: The simple, optimized spectrophotometric assay for PDHc analysis allows reliable investigation of the enzyme complex in human skin fibroblasts. (+info)The SR protein SC35 is responsible for aberrant splicing of the E1alpha pyruvate dehydrogenase mRNA in a case of mental retardation with lactic acidosis. (8/42)
Pyruvate dehydrogenase (PDH) complex deficiency is a major cause of lactic acidosis and Leigh's encephalomyelopathies in infancy and childhood, resulting in early death in the majority of patients. Most of the molecular defects have been localized in the coding regions of the E1alpha PDH gene. Recently, we identified a novel mutation of the E1alpha PDH gene in a patient with an encephalopathy and lactic acidosis. This mutation, located downstream of exon 7, activates a cryptic splice donor and leads to the retention of intronic sequences. Here, we demonstrate that the mutation results in an increased binding of the SR protein SC35. Consistently, ectopic overexpression of this splicing factor enhanced the use of the cryptic splice site, whereas small interfering RNA-mediated reduction of the SC35 protein levels in primary fibroblasts from the patient resulted in the almost complete disappearance of the aberrantly spliced E1alpha PDH mRNA. Our findings open the exciting prospect for a novel therapy of an inherited disease by altering the level of a specific splicing factor. (+info)Pyruvate Dehydrogenase Complex (PDH) Deficiency is a genetic disorder that affects the body's ability to convert certain food molecules into energy. The pyruvate dehydrogenase complex is a group of enzymes that converts pyruvate, a byproduct of glucose metabolism in the cell's cytoplasm, into acetyl-CoA, which then enters the citric acid cycle (also known as the Krebs cycle) in the mitochondria to produce energy in the form of ATP.
PDH deficiency results from mutations in one or more genes encoding the subunits of the PDH complex or its activators, leading to reduced enzymatic activity. This impairs the conversion of pyruvate to acetyl-CoA and causes an accumulation of pyruvate in body tissues and fluids, particularly during periods of metabolic stress such as illness, infection, or fasting.
The severity of PDH deficiency can vary widely, from mild to severe forms, depending on the extent of enzyme dysfunction. Symptoms may include developmental delay, hypotonia (low muscle tone), seizures, poor feeding, and metabolic acidosis. In severe cases, it can lead to neurological damage, lactic acidosis, and early death if not diagnosed and treated promptly.
PDH deficiency is typically diagnosed through biochemical tests that measure the activity of the PDH complex in cultured skin fibroblasts or muscle tissue. Genetic testing may also be used to identify specific gene mutations causing the disorder. Treatment usually involves a low-carbohydrate, high-fat diet and supplementation with thiamine (vitamin B1), which is an essential cofactor for PDH complex activity. In some cases, dialysis or other supportive measures may be necessary to manage metabolic acidosis and other complications.
The Pyruvate Dehydrogenase Complex (PDC) is a multi-enzyme complex that plays a crucial role in cellular energy metabolism. It is located in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate, the end product of glycolysis, into acetyl-CoA. This reaction links the carbohydrate metabolism (glycolysis) to the citric acid cycle (Krebs cycle), enabling the continuation of energy production in the form of ATP through oxidative phosphorylation.
The Pyruvate Dehydrogenase Complex consists of three main enzymes: pyruvate dehydrogenase (E1), dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3). Additionally, two regulatory enzymes are associated with the complex: pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP). These regulatory enzymes control the activity of the PDC through reversible phosphorylation and dephosphorylation, allowing the cell to adapt to varying energy demands and substrate availability.
Deficiencies or dysfunctions in the Pyruvate Dehydrogenase Complex can lead to various metabolic disorders, such as pyruvate dehydrogenase deficiency, which may result in neurological impairments and lactic acidosis due to disrupted energy metabolism.
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.
Dihydrolipoyllysine-residue acetyltransferase is a type of enzyme that plays a crucial role in the cellular process of energy production, specifically in the citric acid cycle (also known as the Krebs cycle or tricarboxylic acid cycle). This enzyme is responsible for transferring an acetyl group from acetyl-CoA to a specific residue on another protein called dihydrolipoyl dehydrogenase.
The reaction catalyzed by this enzyme can be summarized as follows:
Acetyl-CoA + dihydrolipoyl dehydrogenase (E3-DHLA) -> CoA + acetylated-dihydrolipoyl dehydrogenase (E3-DHLAA)
The acetylation of the dihydrolipoyl dehydrogenase protein is a necessary step in the citric acid cycle, which helps generate energy in the form of ATP through a series of oxidation-reduction reactions. Defects or mutations in this enzyme can lead to various metabolic disorders and diseases.
The Ketoglutarate Dehydrogenase Complex (KGDC or α-KGDH) is a multi-enzyme complex that plays a crucial role in the Krebs cycle, also known as the citric acid cycle. It is located within the mitochondrial matrix of eukaryotic cells and functions to catalyze the oxidative decarboxylation of α-ketoglutarate into succinyl-CoA, thereby connecting the Krebs cycle to the electron transport chain for energy production.
The KGDC is composed of three distinct enzymes:
1. α-Ketoglutarate dehydrogenase (E1): This enzyme catalyzes the decarboxylation and oxidation of α-ketoglutarate to form a thioester intermediate with lipoamide, which is bound to the E2 component.
2. Dihydrolipoyl succinyltransferase (E2): This enzyme facilitates the transfer of the acetyl group from the lipoamide cofactor to CoA, forming succinyl-CoA and regenerating oxidized lipoamide.
3. Dihydrolipoyl dehydrogenase (E3): The final enzyme in the complex catalyzes the reoxidation of reduced lipoamide back to its disulfide form, using FAD as a cofactor and transferring electrons to NAD+, forming NADH.
The KGDC is subject to regulation by several mechanisms, including phosphorylation-dephosphorylation reactions that can inhibit or activate the complex, respectively. Dysfunction of this enzyme complex has been implicated in various diseases, such as neurodegenerative disorders and cancer.
Dihydrolipoamide dehydrogenase (DHLD) is an enzyme that plays a crucial role in several important metabolic pathways in the human body, including the citric acid cycle and the catabolism of certain amino acids. DHLD is a component of multi-enzyme complexes, such as the pyruvate dehydrogenase complex (PDC) and the alpha-ketoglutarate dehydrogenase complex (KGDC).
The primary function of DHLD is to catalyze the oxidation of dihydrolipoamide, a reduced form of lipoamide, back to its oxidized state (lipoamide) while simultaneously reducing NAD+ to NADH. This reaction is essential for the continued functioning of the PDC and KGDC, as dihydrolipoamide is a cofactor for these enzyme complexes.
Deficiencies in DHLD can lead to serious metabolic disorders, such as maple syrup urine disease (MSUD) and riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD). These conditions can result in neurological symptoms, developmental delays, and metabolic acidosis, among other complications. Treatment typically involves dietary modifications, supplementation with specific nutrients, and, in some cases, enzyme replacement therapy.
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.
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.
Ketone oxidoreductases are a group of enzymes that catalyze the conversion of ketones to corresponding alcohols or vice versa, through the process of reduction or oxidation. These enzymes play an essential role in various metabolic pathways and biochemical reactions within living organisms.
In the context of medical research and diagnostics, ketone oxidoreductases have gained attention for their potential applications in the development of biosensors to detect and monitor blood ketone levels, particularly in patients with diabetes. Elevated levels of ketones in the blood (known as ketonemia) can indicate a serious complication called diabetic ketoacidosis, which requires prompt medical attention.
One example of a ketone oxidoreductase is the enzyme known as d-beta-hydroxybutyrate dehydrogenase (d-BDH), which catalyzes the conversion of d-beta-hydroxybutyrate to acetoacetate. This reaction is part of the metabolic pathway that breaks down fatty acids for energy production, and it becomes particularly important during periods of low carbohydrate availability or insulin deficiency, as seen in diabetes.
Understanding the function and regulation of ketone oxidoreductases can provide valuable insights into the pathophysiology of metabolic disorders like diabetes and contribute to the development of novel therapeutic strategies for their management.
Thiamine pyrophosphate (TPP) is the active form of thiamine (vitamin B1) that plays a crucial role as a cofactor in various enzymatic reactions, particularly in carbohydrate metabolism. TPP is essential for the functioning of three key enzymes: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase. These enzymes are involved in critical processes such as the conversion of pyruvate to acetyl-CoA, the oxidative decarboxylation of alpha-ketoglutarate in the Krebs cycle, and the pentose phosphate pathway, which is important for generating reducing equivalents (NADPH) and ribose sugars for nucleotide synthesis. A deficiency in thiamine or TPP can lead to severe neurological disorders, including beriberi and Wernicke-Korsakoff syndrome, which are often observed in alcoholics due to poor nutrition and impaired thiamine absorption.
Thioctic acid is also known as alpha-lipoic acid. It is a vitamin-like chemical compound that is made naturally in the body and is found in small amounts in some foods like spinach, broccoli, and potatoes. Thioctic acid is an antioxidant that helps to protect cells from damage caused by free radicals. It also plays a role in energy production in the cells and has been studied for its potential benefits in the treatment of diabetes and nerve-related symptoms of diabetes such as pain, burning, itching, and numbness. Thioctic acid is available as a dietary supplement.
Medical Definition: Thioctic acid (also known as alpha-lipoic acid) is a vitamin-like antioxidant that is made naturally in the body and is found in small amounts in some foods. It plays a role in energy production in the cells, and has been studied for its potential benefits in the treatment of diabetes and nerve-related symptoms of diabetes such as pain, burning, itching, and numbness. Thioctic acid is also available as a dietary supplement.
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.
Pyruvic acid, also known as 2-oxopropanoic acid, is a key metabolic intermediate in both anaerobic and aerobic respiration. It is a carboxylic acid with a ketone functional group, making it a β-ketoacid. In the cytosol, pyruvate is produced from glucose during glycolysis, where it serves as a crucial link between the anaerobic breakdown of glucose and the aerobic process of cellular respiration in the mitochondria.
During low oxygen availability or high energy demands, pyruvate can be converted into lactate through anaerobic glycolysis, allowing for the continued production of ATP (adenosine triphosphate) without oxygen. In the presence of adequate oxygen and functional mitochondria, pyruvate is transported into the mitochondrial matrix where it undergoes oxidative decarboxylation to form acetyl-CoA by the enzyme pyruvate dehydrogenase complex (PDC). This reaction also involves the reduction of NAD+ to NADH and the release of CO2. Acetyl-CoA then enters the citric acid cycle, where it is further oxidized to produce energy in the form of ATP, NADH, FADH2, and GTP (guanosine triphosphate) through a series of enzymatic reactions.
In summary, pyruvic acid is a vital metabolic intermediate that plays a significant role in energy production pathways, connecting glycolysis to both anaerobic and aerobic respiration.
Pyruvate is a negatively charged ion or group of atoms, called anion, with the chemical formula C3H3O3-. It is formed from the decomposition of glucose and other sugars in the process of cellular respiration. Pyruvate plays a crucial role in the metabolic pathways that generate energy for cells.
In the cytoplasm, pyruvate is produced through glycolysis, where one molecule of glucose is broken down into two molecules of pyruvate, releasing energy and producing ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide).
In the mitochondria, pyruvate can be further metabolized through the citric acid cycle (also known as the Krebs cycle) to produce more ATP. The process involves the conversion of pyruvate into acetyl-CoA, which then enters the citric acid cycle and undergoes a series of reactions that generate energy in the form of ATP, NADH, and FADH2 (reduced flavin adenine dinucleotide).
Overall, pyruvate is an important intermediate in cellular respiration and plays a central role in the production of energy for cells.
Dichloroacetic acid (DCA) is a chemical compound with the formula CCl2CO2H. It is a colorless liquid that is used as a reagent in organic synthesis and as a laboratory research tool. DCA is also a byproduct of water chlorination and has been found to occur in low levels in some chlorinated drinking waters.
In the medical field, DCA has been studied for its potential anticancer effects. Preclinical studies have suggested that DCA may be able to selectively kill cancer cells by inhibiting the activity of certain enzymes involved in cell metabolism. However, more research is needed to determine whether DCA is safe and effective as a cancer treatment in humans.
It is important to note that DCA is not currently approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) for use as a cancer treatment. It should only be used in clinical trials or under the supervision of a qualified healthcare professional.
Acetyltransferases are a type of enzyme that facilitates the transfer of an acetyl group (a chemical group consisting of an acetyl molecule, which is made up of carbon, hydrogen, and oxygen atoms) from a donor molecule to a recipient molecule. This transfer of an acetyl group can modify the function or activity of the recipient molecule.
In the context of biology and medicine, acetyltransferases are important for various cellular processes, including gene expression, DNA replication, and protein function. For example, histone acetyltransferases (HATs) are a type of acetyltransferase that add an acetyl group to the histone proteins around which DNA is wound. This modification can alter the structure of the chromatin, making certain genes more or less accessible for transcription, and thereby influencing gene expression.
Abnormal regulation of acetyltransferases has been implicated in various diseases, including cancer, neurodegenerative disorders, and infectious diseases. Therefore, understanding the function and regulation of these enzymes is an important area of research in biomedicine.
Pyruvate dehydrogenase deficiency
Pyruvate dehydrogenase
List of MeSH codes (C16)
Pyruvate dehydrogenase complex
List of MeSH codes (C18)
List of MeSH codes (C10)
Pyruvate dehydrogenase (lipoamide) beta
E3 binding protein
List of dog diseases
Dihydrolipoyl transacetylase
Pyruvate dehydrogenase (lipoamide) alpha 1
Thiamine pyrophosphate
Branched-chain alpha-keto acid dehydrogenase complex
Arsenic biochemistry
Thiamine deficiency
Ketogenic diet
Leigh syndrome
Pyruvate dehydrogenase kinase
Maple syrup urine disease
Dihydrolipoamide dehydrogenase
Melarsoprol
Branched-chain amino acid
Hemolytic anemia
Nicotinamide adenine dinucleotide
Radical SAM
Glycerol kinase deficiency
Cholestasis
Thiamine
Chromosome 8
Red blood cell
Pyruvate dehydrogenase deficiency - Wikipedia
Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency-Results from a nationwide population-based study |...
Treatment of congenital lactic acidosis with dichloroacetate | Archives of Disease in Childhood
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Components of the pyruvate dehydro4
- PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). (wikipedia.org)
- Other components of the pyruvate dehydrogenase complex are also involved in pyruvate dehydrogenase deficiency. (medlineplus.gov)
- PDCD is caused by abnormalities in the genes that encode the components of the pyruvate dehydrogenase complex. (brainandnervecenter.com)
- Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g. (beds.ac.uk)
Metabolism24
- Pyruvate dehydrogenase deficiency (also known as pyruvate dehydrogenase complex deficiency or PDCD or PDH deficiency) is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. (wikipedia.org)
- The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. (wikipedia.org)
- Pathways of pyruvate metabolism and oxidative phosphorylation. (bmj.com)
- Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency, or mitochondrial respiratory chain disorders. (bvsalud.org)
- Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). (brainandnervecenter.com)
- Untangling the Spirals of Metabolic Disease: Primary Diagnoses and Secondary Effects: Implications for Treatment David A. H. Whiteman MD 1909 Archibald Garrod In his paper, Inborn Errors of Metabolism, the disease Alkaptonuria (Ochronosis: Homogentisic Acid Oxidase Deficiency) is described as being caused by a gene. (abcdocz.com)
- The phenotype results from a defect in amino acid metabolism and not from a defect in pyruvate dehydrogenase. (blogspot.com)
- Some inherited metabolic disorders may alter pyruvate metabolism indirectly. (nih.gov)
- Disorders in pyruvate metabolism appear to lead to deficiencies in neurotransmitter synthesis and, consequently, to nervous system disorders. (nih.gov)
- Mutations in genes encoding any of the 3 pyruvate dehydrogenase complex (PDHC) enzymes are inborn errors of mitochondrial energy metabolism. (medscape.com)
- A deficiency in any one of the enzymes involved in pyruvate metabolism leads to one of many disorders. (msdmanuals.com)
- In many pyruvate metabolism disorders, both parents of the affected child carry a copy of the abnormal gene. (msdmanuals.com)
- Many enzymes are involved in pyruvate metabolism. (msdmanuals.com)
- Symptoms of pyruvate metabolism disorders may develop any time between early infancy and late adulthood. (msdmanuals.com)
- This leads to a secondary functional deficiency of a number of ETF-dependent dehydrogenases and results in a combined disorder of both fatty acid oxidation and amino acid metabolism (especially lysine, tryptophan, and branched-chain amino acids). (nature.com)
- This battery of measurements are used in the diagnosis and treatment of certain liver, heart, and kidney diseases, acid-base imbalance in the respiratory and metabolic systems, other diseases involving lipid metabolism and various endocrine disorders as well as other metabolic or nutritional disorders. (cdc.gov)
- Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism . (arizona.edu)
- Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. (molcells.org)
- Mitochondrial Ca 2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. (molcells.org)
- Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. (molcells.org)
- Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. (molcells.org)
- Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. (molcells.org)
- T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. (molcells.org)
- This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases. (molcells.org)
Mutations18
- More rarely, mutations occur in the E2 (dihydrolipoyl transacetylase) or the E3 (dihydrolipoyl dehydrogenase) subunits of the PDC enzymatic complex, DLAT and DLD genes respectively. (wikipedia.org)
- Most identifiable cases involve inherited or spontaneous mutations in the pyruvate dehydrogenase complex (PDC) or in one or more enzymes of the respiratory chain. (bmj.com)
- Mutations in the gene that provides instructions for making E1 alpha, the PDHA1 gene, are the most common cause of pyruvate dehydrogenase deficiency, accounting for approximately 80 percent of cases. (medlineplus.gov)
- Mutations in the genes that provide instructions for E1 beta (the PDHB gene), the E2 enzyme (the DLAT gene), E3 binding protein (the PDHX gene), and pyruvate dehydrogenase phosphatase (the PDP1 gene) have been identified in people with this condition. (medlineplus.gov)
- Although it is unclear how mutations in each of these genes affect the complex, reduced functioning of one component of the complex appears to impair the activity of the whole complex. (medlineplus.gov)
- As with PDHA1 gene mutations, changes in these other genes lead to a reduction of pyruvate dehydrogenase complex activity. (medlineplus.gov)
- INTRODUCTION: Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon. (bvsalud.org)
- A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex. (bvsalud.org)
- Is the mitochondrial complex I ND5 gene a hotspot for MELAS causing mutations? (ima-press.net)
- Mutations in E1, E2, or E3 cause maple syrup urine disease. (medscape.com)
- No clear genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exemption of mutations in E2, which cause thiamine-responsive maple syrup urine disease. (medscape.com)
- Mutations in E3 cause additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenases. (medscape.com)
- Defects in ELECTRON TRANSPORT COMPLEX IV can be caused by mutations in the SURF1, SCO2, COX10, or SCO1 genes. (uams.edu)
- It's likely that other mutations are embryonic lethals so we never see them as genetic diseases [ Most Metabolic Diseases Affect Unimportant Genes ]. (blogspot.com)
- Mutations in this gene have been identified in patients with E3-deficient maple syrup urine disease and lipoamide dehydrogenase deficiency. (thermofisher.com)
- Mutations in the DLD gene cause dihydrolipoamide dehydrogenase deficiency. (blogspot.com)
- Mutations in the DLD gene impair the function of the DLD enzyme, which prevents the three enzyme complexes from functioning properly. (blogspot.com)
- Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto Y. ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome . (arizona.edu)
Genes3
- All of these genes, like the PDHA1 gene are responsible for coding for a specific subunit of the pyruvate dehydrogenase complex. (wikipedia.org)
- The genes involved in pyruvate dehydrogenase deficiency each provide instructions for making a protein that is a component of a group of proteins called the pyruvate dehydrogenase complex. (medlineplus.gov)
- What genes are related to dihydrolipoamide dehydrogenase deficiency? (blogspot.com)
Dihydrolipoamide13
- The resulting hydroxyethyl-TPP complex reacts with oxidised lipoamide (LipS 2 ), the prosthetic group of dihydrolipoamide transacetylase (E 2 ), to form acetyl lipoamide. (bmj.com)
- The cycle of reaction is completed when reduced lipoamide is reoxidised by the flavoprotein, dihydrolipoamide dehydrogenase (E 3 ). (bmj.com)
- The L protein, also named dihydrolipoamide dehydrogenase, is also a component of the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and the branched-chain alpha-keto acide dehydrogenase complex. (thermofisher.com)
- Dihydrolipoamide dehydrogenase deficiency is a severe condition that can affect several body systems. (blogspot.com)
- A common feature of dihydrolipoamide dehydrogenase deficiency is a potentially life-threatening buildup of lactic acid in tissues (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. (blogspot.com)
- Liver problems can also occur in dihydrolipoamide dehydrogenase deficiency, ranging from an enlarged liver (hepatomegaly) to life-threatening liver failure. (blogspot.com)
- Typically, the signs and symptoms of dihydrolipoamide dehydrogenase deficiency occur in episodes that may be triggered by fever, injury, or other stresses on the body. (blogspot.com)
- How common is dihydrolipoamide dehydrogenase deficiency? (blogspot.com)
- Dihydrolipoamide dehydrogenase deficiency occurs in an estimated 1 in 35,000 to 48,000 individuals of Ashkenazi Jewish descent. (blogspot.com)
- In other populations, the prevalence of dihydrolipoamide dehydrogenase deficiency is unknown, but the condition is likely rare. (blogspot.com)
- This gene provides instructions for making an enzyme called dihydrolipoamide dehydrogenase (DLD). (blogspot.com)
- The brain is especially affected by the buildup of molecules and the lack of cellular energy, resulting in the neurological problems associated with dihydrolipoamide dehydrogenase deficiency. (blogspot.com)
- How do people inherit dihydrolipoamide dehydrogenase deficiency? (blogspot.com)
Lactate11
- Excess pyruvate is then converted into lactic acid by lactate dehydrogenase. (wikipedia.org)
- Under aerobic conditions, the activity of PDC determines the rate at which all cells oxidise glucose, pyruvate, and lactate. (bmj.com)
- Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis and lipogenesis, or for oxidation to acetyl CoA by the pyruvate dehydrogenase (PDH) complex (PDC). (bmj.com)
- Pyruvate and lactate were elevated. (bvsalud.org)
- The clinical presentation combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurologic presentations. (bvsalud.org)
- The accumulation of lactate is due to the fact that it can't be converted to pyruvate because the defect in pyruvate dehydrogenase causes buildup of pyruvate in the cell [ Pyruvate ]. (blogspot.com)
- The drug may also be helpful to alleviate lactate acidosis in nongenetic conditions, such as asphyxia , liver disease, and ischemia. (medscape.com)
- 2003). Biochemically, this disease is characterized by increases in serum pyruvate and lactate, a normal lactate/pyruvate ratio, and normal pyruvate dehydrogenase activity. (preventiongenetics.com)
- The diagnostic workup for a mitochondrial disorder may include testing to demonstrate elevations of the lactate-to-pyruvate ratio and an elevated growth differentiation factor 15 concentration. (mayocliniclabs.com)
- Consider LAPYP / Lactate Pyruvate Panel, Plasma and GDF15 / Growth Differentiation Factor 15, Plasma. (mayocliniclabs.com)
- Serum and CSF lactate is elevated and decreased activity of the pyruvate dehydrogenase complex is present. (arizona.edu)
Kinase13
- Other associated proteins control the activity of the complex: pyruvate dehydrogenase phosphatase turns on (activates) the complex, while pyruvate dehydrogenase kinase turns off (inhibits) the complex. (medlineplus.gov)
- TK2d "Virtual" Support Meeting Are you or your loved one impacted by TK2 (Thymidine Kinase 2) deficiency? (umdf.org)
- The BCKD enzyme complex, which is associated with the inner mitochondrial membrane, has 3 different catalytic components (ie, E1, E2, E3) and 2 associated regulatory enzymes (ie, BCKD phosphatase, BCKD kinase). (medscape.com)
- As a therapeutic, its principal mechanism of action is to inhibit pyruvate dehydrogenase kinase (PDK). (srcinhibitors.com)
- Pyruvate kinase deficiency, one of the most common enzymatic defects of the erythrocyte, manifests clinically as a hemolytic anemia that can range from a mildly compensated anemia to severe anemia of childhood. (medscape.com)
- An international, multicenter registry that collected clinical data on patients with pyruvate kinase deficiency found that 93% of newborns were treated with phototherapy, and 46% were treated with exchange transfusions. (medscape.com)
- Peripheral blood smear in a child with splenectomy and pyruvate kinase deficiency. (medscape.com)
- The enzyme activity rate in most patients with pyruvate kinase deficiency is 5-25% of normal, with measurement of the intermediates (2,3-diphosphoglycerol and glucose-6-phosphate) proximal to the enzyme defect helping to confirm the diagnosis. (medscape.com)
- Enzyme assay, as well as deoxyribonucleic acid (DNA) analysis with a polymerase chain reaction (PCR) assay or single-strand conformation polymorphism, can also be used to confirm the diagnosis of pyruvate kinase deficiency. (medscape.com)
- In patients with mild to moderate pyruvate kinase deficiency, care is predominantly supportive. (medscape.com)
- Mitapivat is the first disease-modifying therapy approved for hemolytic anemia in adults with pyruvate kinase deficiency. (medscape.com)
- It improves hemoglobin values and reduces transfusion burden in patients with pyruvate kinase deficiency by targeting the underlying defect. (medscape.com)
- Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca 2+ flux. (molcells.org)
PDCD4
- Project Abstract/Summary Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is a rare disease of mitochondrial energy failure in which the life expectancy of affected children is severely truncated from unrelenting lactic acidosis and/or from progressive neurological and neuromuscular degeneration. (sbir.gov)
- The U.S. Food and Drug Administration (FDA) has just confirmed a virtual FDA listening session, co-hosted by the United Mitochondrial Disease Foundation and MitoAction, focused on Pyruvate Dehydrogenase Complex Deficiency (PDCD). (umdf.org)
- Not all individuals with PDCD are affected at birth, but almost all show signs of the disease during their first year of life. (brainandnervecenter.com)
- PDCD is most commonly caused by abnormalities in the gene that encodes the E1 alpha subunit, E1-alpha subunit pyruvate dehydrogenase gene or PDHA1. (brainandnervecenter.com)
Patients with pyruvate1
- Support and fund the development of life-saving treatment for patients with pyruvate dehydrogenase complex deficiency and related genetic diseases. (globalgenes.org)
Phosphatase4
- Pyruvate dehydrogenase phosphatase deficiency is a very rare subtype of pyruvate dehydrogenase deficiency (PDHD see this term) characterized by lactic acidemia in the neonatal period. (globalgenes.org)
- Newly diagnosed with Pyruvate dehydrogenase phosphatase deficiency? (globalgenes.org)
- PYRUVATE DEHYDROGENASE ( LIPOAMIDE )- PHOSPHATASE catalyzes reactivation of the complex. (nih.gov)
- An increase in serum phosphatase activity is associated with primary hyperparathyroidism, secondary hyperparathyroidism owing to chronic renal disease, rickets, and osteitis deformans juvenilia due to vitamin D deficiency and malabsorption or renal tubular dystrophies. (cdc.gov)
Alpha-ketoglutarate1
- The E3 component is associated with 2 additional alpha-ketoacid dehydrogenase complexes, namely pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. (medscape.com)
Enzymes8
- 2 4 A few cases have been reported that involve deficiencies in enzymes of the tricarboxylic acid cycle, such as fumarase, or of gluconeogenesis, such as pyruvate carboxylase (PC) or phosphoenolpyruvate carboxykinase (PEPCK). (bmj.com)
- The pyruvate dehydrogenase complex is made up of multiple copies of several enzymes called E1, E2, and E3, each of which performs part of the chemical reaction that converts pyruvate to acetyl-CoA. (medlineplus.gov)
- The age of onset and severity of disease depends on the activity level of the PDC enzymes. (brainandnervecenter.com)
- The E 3 subunit is shared with two other enzymes: 2-oxoglutarate dehydrogenase (a citric acid cycle enzyme) and 2-oxo acid dehydrogenase (a enzyme required for amino acid degradation) [ Pyruvate Dehydrogenase Evolution ]. (blogspot.com)
- A hereditary deficiency in any one of these enzymes results in one of a variety of disorders, depending on which enzyme is deficient. (msdmanuals.com)
- This disorder is caused by a lack of a group of enzymes needed to process pyruvate. (msdmanuals.com)
- DLD is one component of three different groups of enzymes that work together (enzyme complexes): branched-chain alpha-keto acid dehydrogenase (BCKD), pyruvate dehydrogenase (PDH), and alpha (α)-ketoglutarate dehydrogenase (αKGDH). (blogspot.com)
- 3 2 Under physiological hypoxia, low oxygen levels lead to reduced activity of succinate dehydrogenase (SDH), which metabolizes succinate, and other oxygen-dependent enzymes in the electron transport chain, causing succinate accumulation. (haematologica.org)
Disorders3
- Within the category of intractable epilepsy, there are many different seizure disorders, many of which are rare diseases. (myketocal.com)
- KetoCal is also used by individuals with rare metabolic disorders that are managed with a ketogenic diet, including GLUT1 Deficiency Syndrome and Pyruvate Dehydrogenase Deficiency (PDHD). (myketocal.com)
- Some specific pyruvate disorders are helped by changes in diet. (msdmanuals.com)
Oxidative phosphorylation1
- Some forms of combined oxidative phosphorylation deficiency can present as Leigh syndrome (see, e.g., 617664). (beds.ac.uk)
Enzyme activity3
- We also provide a biochemical service to measure Pyruvate Dehydrogenase (PDH) enzyme activity in cultured fibroblasts. (ouh.nhs.uk)
- Deficiencies in the enzyme activity lead to accumulation of breakdown products that are secreted in the urine. (blogspot.com)
- The researchers found that phenylbutyrate increased PDHC enzyme activity in fibroblasts from patients with PDHC deficiency. (medscape.com)
Subunits1
- The E1 enzyme, also called pyruvate dehydrogenase, is composed of four parts (subunits): two alpha subunits (called E1 alpha) and two beta subunits (called E1 beta). (medlineplus.gov)
Clinical8
- citation needed] The clinical presentation of congenital PDH deficiency is typically characterized by heterogenous neurological features that usually appear within the first year of life. (wikipedia.org)
- The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. (lu.se)
- For a list of clinical trials in this disease area, please click here . (globalgenes.org)
- CONCLUSION: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. (bvsalud.org)
- Given that phenylbutyrate is a drug already approved for use in humans, and its safety profile is well known, these findings have the potential to be rapidly translated to clinical trials for patients with PDHC deficiency," the researchers write. (medscape.com)
- At the present time, clinical sensitivity for MPC1 -associated Mitochondrial Pyruvate Carrier Deficiency is difficult to estimate as fewer than ten cases have been described in the literature. (preventiongenetics.com)
- Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for nuclear mitochondrial disease. (mayocliniclabs.com)
- Objective To expand the spectrum of glucose transporter type 1 deficiency syndromes with a novel clinical and radiological phenotype not associated with microcephaly. (jamanetwork.com)
Symptoms8
- Females with residual pyruvate dehydrogenase activity will have no uncontrollable systemic lactic acidosis and few, if any, neurological symptoms. (wikipedia.org)
- The following table lists common symptoms of pyruvate dehydrogenase deficiency. (wikipedia.org)
- What are the symptoms for pyruvate dehydrogenase deficiency? (brainandnervecenter.com)
- If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. (brainandnervecenter.com)
- Moreover, in a zebrafish model of PDHC deficiency, the drug restored enzyme levels and alleviated symptoms of lethargy and hyperpigmentation. (medscape.com)
- This deficiency results in a variety of symptoms, ranging from mild to severe. (msdmanuals.com)
- Classic maple syrup urine disease (MSUD) is the most common form, with symptoms developing in neonates aged 4-7 days, depending on feeding regimen. (medscape.com)
- MPC1 sequencing should be considered in patients with a family history of Mitochondrial Pyruvate Carrier Deficiency (MPYCD) or patients who present with symptoms consistent with MPYCD. (preventiongenetics.com)
PDHA11
- We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. (bvsalud.org)
PDHX1
- The final gene that could be responsible for this disease is the PDHX gene, which codes for the E3 binding protein which is responsible for binding E3 dimers to the E2 subunit of the complex. (wikipedia.org)
Respiratory2
- Reducing equivalents (NADH, FADH 2 ) are generated by reactions catalysed by the PDC and the tricarboxylic acid cycle and donate electrons (e - ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (complex I) or at succinate ubiquinone oxidoreductase (complex II). (bmj.com)
- Samanta D, Gokden M. PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex. (uams.edu)
Glucose2
- The first phase of respiration is glycolysis, a series of ten biochemical reactions in the cytoplasm that convert glucose into pyruvate. (wikipedia.org)
- Are they missing some co-factors for the actual pyruvate dehydrogenase complex to work, so they can process glucose or fatty acids. (drweitz.com)
Gluconeogenesis1
- They are difficult to diagnose and describe because pyruvate is a key intermediate in glycolysis, gluconeogenesis, and the tricarboxylic acid cycle. (nih.gov)
Biochemical1
- Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights. (viictr.org)
Multienzyme complex2
Mitochondria4
- Pyruvate is then transported into mitochondria, where it is converted by the pyruvate dehydrogenase complex into acetyl-CoA, the starting substrate of the Krebs cycle. (wikipedia.org)
- Are you missing some of the things that stabilize complex 2 in your mitochondria? (drweitz.com)
- 2012). The MPC1 gene encodes for an inner mitochondrial membrane protein that interacts with MPC2 (BRP44) to form the multimeric mitochondrial pyruvate carrier complex essential for transport of pyruvate into the mitochondria. (preventiongenetics.com)
- Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca 2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. (molcells.org)
Buildup2
- Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. (medlineplus.gov)
- Problems with the breaking down (metabolizing) of pyruvate can limit a cell's ability to produce energy and allow a buildup of a waste product called lactic acid (lactic acidosis). (msdmanuals.com)
Congenital2
- A disease that results from a congenital defect in ELECTRON TRANSPORT COMPLEX IV. (uams.edu)
- As an investigational drug for numerous congenital and acquired diseases, DCA is administered orally or parenterally, usually at doses of 10-50mg/kg per day. (srcinhibitors.com)
Maple syrup u11
- Maple syrup urine disease (MSUD), also known as branched-chain ketoaciduria, is an aminoacidopathy due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. (medscape.com)
- Consequently, maple syrup urine disease has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with maple syrup urine disease have better outcomes compared with infants who are diagnosed after they become symptomatic. (medscape.com)
- [ 4 ] In 1960, Dancis et al demonstrated that the enzymatic defect in maple syrup urine disease was at the level of the decarboxylation of the branched-chain amino acids. (medscape.com)
- [ 5 ] Snyderman et al initiated the first successful dietary treatment of maple syrup urine disease by restricting oral intake of branched-chain amino acids. (medscape.com)
- [ 6 ] In 1971, Scriver et al reported the first case of thiamine-responsive maple syrup urine disease. (medscape.com)
- Maple syrup urine disease is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex, which catalyses the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoAs. (medscape.com)
- Maple syrup urine disease occurs in about 1 case per 185,000 live births. (medscape.com)
- As an autosomal recessive disorder, maple syrup urine disease is more prevalent in populations with a high occurrence of consanguinity. (medscape.com)
- Infants with untreated early onset (ie, classic) maple syrup urine disease have significant developmental delay and die within the first months of life. (medscape.com)
- Phenylbutyrate is already used to treat a related metabolic disorder, maple syrup urine disease . (medscape.com)
- Given similarities between the biochemistry involved in maple syrup urine disease and PDHC, the researchers hypothesized that the drug might be effective in patients with PDHC deficiency. (medscape.com)
Abnormal1
- The abnormal urinary loss of TRYPTOPHAN, a precursor of NIACIN, leads to a NICOTINAMIDE deficiency, PELLAGRA-like light-sensitive rash, CEREBELLAR ATAXIA, emotional instability, and aminoaciduria. (uchicago.edu)
Mitochondrial Diseases1
- It is suggested that mitochondrial diseases might be identified in 22-33% of cryptogenic stroke cases in young subjects. (ima-press.net)
Gene6
- The PDHB gene is responsible for the coding of the E1 beta subunit of the pyruvate dehydrogenase complex. (wikipedia.org)
- Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene he will develop the disease. (brainandnervecenter.com)
- Quental et al identified a homozygous 1-bp deletion (117delC) in the BCKDHA gene (this gene codes for the alpha subunit of the BCKD enzyme complex, specifically E1) in Portuguese Gypsies and estimated the carrier frequency for this deletion to be as high as 1.4% (about 1 case per 71 live births). (medscape.com)
- There are many alleles of this gene and some of them cause genetic diseases. (blogspot.com)
- Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the FRMPD4 gene. (nih.gov)
- As MPC1 (formerly BRP44L) gene defects have only recently been linked to MPYCD and few cases have been described to date, global incidence and long-term prognosis for this disease are currently unknown. (preventiongenetics.com)
Diagnosis7
- This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. (bvsalud.org)
- A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency. (bvsalud.org)
- Liu N , Sun Q . Laboratory Diagnosis of Cerebral Creatine Deficiency Syndromes by Determining Creatine and Guanidinoacetate in Plasma and Urine. (viictr.org)
- Alanine aminotransferase measurements are used in the diagnosis and treatment of certain liver diseases (e.g., viral hepatitis and cirrhosis) and heart diseases. (cdc.gov)
- Albumin measurements are used in the diagnosis and treatment of numerous diseases primarily involving the liver or kidneys. (cdc.gov)
- AST measurements are used in the diagnosis and treatment of certain types of liver and heart disease. (cdc.gov)
- BUN measurements are used in the diagnosis of certain renal and metabolic diseases. (cdc.gov)
Cytochrome4
- Cytochrome c oxidase (complex IV) catalyses the reduction of molecular oxygen to water and ATP synthase (complex V) generates ATP from ADP. (bmj.com)
- Cytochrome-c Oxidase Deficiency" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (uams.edu)
- This graph shows the total number of publications written about "Cytochrome-c Oxidase Deficiency" by people in UAMS Profiles by year, and whether "Cytochrome-c Oxidase Deficiency" was a major or minor topic of these publications. (uams.edu)
- Below are the most recent publications written about "Cytochrome-c Oxidase Deficiency" by people in Profiles over the past ten years. (uams.edu)
Disorder4
- Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. (brainandnervecenter.com)
- In humans, acetoacetyl-CoA is involved in the metabolic disorder called the short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (HADH) pathway. (hmdb.ca)
- Mitochondrial Pyruvate Carrier Deficiency (MPYCD) is a rare disorder of mitochondrial pyruvate oxidation (Bricker et al. (preventiongenetics.com)
- MPYCD is an autosomal recessive disorder caused by defects in the mitochondrial pyruvate carrier complex (Bricker et al. (preventiongenetics.com)
Adulthood2
- Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood. (medlineplus.gov)
- In some affected people, liver disease, which can begin anytime from infancy to adulthood, is the primary symptom. (blogspot.com)
Severe2
- MCAD Deficiency A Child with Multiple Problems The Pregnancy Complicated by abdominal pain, severe nausea and vomiting, "black out spells" Emergency C-section because of maternal hemorrhage (unknown cause) A Child with Multiple Problems The Child Multiple hospital admissions for vomiting and dehydration in first year of life Nissen fundoplication at 18 months of age. (abcdocz.com)
- Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. (nature.com)
Binding protein1
- One of these proteins, E3 binding protein, attaches E3 to the complex and provides the correct structure for the complex to perform its function. (medlineplus.gov)
Branched-chain1
- Recall that the E 3 subunit of PDC is shared with 2-oxo acid dehydrogenase, an enzyme required for the breakdown of branched chain amino acids. (blogspot.com)
Liver disease3
- This population typically has liver disease as the primary symptom. (blogspot.com)
- Serum elevations of ALT activity are rarely observed except in parenchymal liver disease, since ALT is a more liver-specific enzyme than aspartate aminotransferase (AST). (cdc.gov)
- It is currently the most sensitive enzymatic indicator of liver disease, with normal values rarely found in the presence of hepatic disease. (cdc.gov)
Abolished by mutation1
- When PDC activity is reduced or abolished by mutation, pyruvate levels rise. (wikipedia.org)
Dephosphorylation1
- This dephosphorylation activates the complex. (wikipedia.org)
Metabolic Diseases1
- Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. (molcells.org)
PDHc3
- We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development. (lu.se)
- PDHC deficiency currently has no treatment. (medscape.com)
- The drug increased enzyme levels in many tissues, including the brain, suggesting that it might be helpful in treating PDHC deficiency in humans. (medscape.com)
