Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry

Metabolism and Genetic Disorders

Works Count: 185209

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Description

This cluster of papers covers a wide range of topics related to metabolic disorders and biochemical genetics, including newborn screening, mitochondrial function, carnitine metabolism, phenylketonuria, tandem mass spectrometry, inborn errors of metabolism, tyrosine hydroxylase activity, and tetrahydrobiopterin biosynthesis. The papers discuss various aspects of diagnosis, management, and treatment of these disorders.

Keywords

Metabolic Disorders; Biochemical Genetics; Newborn Screening; Mitochondrial Function; Carnitine; Phenylketonuria; Tandem Mass Spectrometry; Inborn Errors of Metabolism; Tyrosine Hydroxylase; Tetrahydrobiopterin

[99] Determination of nucleic acids in tissues by pentose analysis

1957-01-01

Walter Schneider

The estimation of glycogen with the anthrone reagent.

1950-01-01

Sam Seifter , S Dayton

A PHOTOMETRIC ADAPTATION OF THE SOMOGYI METHOD FOR THE DETERMINATION OF GLUCOSE

1944-05-01

Norton Nelson

The reliability of the various Somogyi-Shaffer-Hartmann (1, 2) copper reagents for glucose determination in biological material has been established. Adaptation of these reagents to calorimetric use may be accomplished by … The reliability of the various Somogyi-Shaffer-Hartmann (1, 2) copper reagents for glucose determination in biological material has been established. Adaptation of these reagents to calorimetric use may be accomplished by omission of the iodide and iodate in their preparation, since these interfere with the molybdate color reagents. This omission produces no especial change in the character of the reagents. KI, however, inhibits the autoreduction of the copper and in its absence an unstable reagent results. Nevertheless, if the copper is added to the rest of the reagent on the day of its use, this difficulty is avoided. When the Somogyi micro reagent (2) is used in this way with almost any of the various phosphomolybdate reagents, very satisfactory proportionality is found between color density and glucose taken over a wide range of values. However, all of the phosphomolybdate reagents tried left much to be desired in reproducibility from time to time and lacked the desired stability of color. We therefore tried various color reagents, which led to the development of a new arsenomolybdate reagent. When this reagent was used with Somogyi’s micro reagent, it gave satisfactory stability and reproducibility of color. By this means it has been possible to utilize the copper reagents in a photometric procedure for practically all the uses to which the titrimetric procedures are adapted. These include tissue sugar, glycogen, urine reduction equivalent, maltose, glucuronic acid, etc. However, diastase determinations have not been successful because of the effect of the undigested starch on the clarity of the final colored solution. The reactions involved in the molybdenum blue reaction are uncertain and beyond the scope of this report. Woods and Mellon (3) discuss and give references to the various interpretations of the reaction. Reagents-Analytical reagent grade or the equivalent. 1. Copper Reagent A. Dissolve 25 gm. of N&C03 (anhydrous), 25 gm. of Rochelle salt, 20 gm. of NaHCOs, and 200 gm. of NaiSOa (anhydrous) in about 800 ml. of water and dilute to 1 liter. Filter if necessary.’ This

Mammalian Protein Metabolism

1964-01-01

Hamish N. Munro , J. B. Allison

Eine neue Bestimmung der Neutralfette im Blutserum und Gewebe

1966-03-01

M. Eggstein , F. H. Kreutz

Fetal and Neonatal Physiology

1989-02-01

Richard A. Polin , William W. Fox , Steven H. Abman

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Tietz Textbook of Clinical Chemistry

1999-07-01

edited byCarl A. Burtis , Edward A. Ashwood

Part I: Laboratory Principles. General Laboratory Techniques and Procedures. Specimen Collection and Processing, Sources of Biological Variation. Part II: Analytical Techniques and Instrumentation. Spectrophotometric Techniques. Fluorometry, Nephelometry, And Turbidimetry. Basic … Part I: Laboratory Principles. General Laboratory Techniques and Procedures. Specimen Collection and Processing, Sources of Biological Variation. Part II: Analytical Techniques and Instrumentation. Spectrophotometric Techniques. Fluorometry, Nephelometry, And Turbidimetry. Basic Principles of Radioactivity and Its Measurement. Electrochemistry. Electrophoresis. Chromatography/Mass Spectrometry. Principlesof Immunochemical Techniques. Automation in the Clinical Laboratory. Part III: Chemometrics. Statistical Procedures. Selection and Interpretation of Laboratory Procedures. Selection and Evaluation of Methods. Establishment and Use of Reference Values. Part IV: Laboratory Management. Clinical Laboratory Informatics. Laboratory Management. Quality Management. Part V: Analytes. Nucleic Acid Biochemistry and Diagnostic Applications. Amino Acids. Proteins. Cytokines. Clinical Enzymology. Tumour Markers. Carbohydrates. Lipids, Lipoproteins, And Apolipoproteins. Therapeutic Drug Monitoring. Clinical Toxicology. Toxic Metals. Vitamins. Trace Elements. Electrolytes and Blood Gases. Part VI: Pathophysiology. Physiology and Disorders of Wates, Electrolyte, And Acid-Base Metabolism. Liver Function. Cardiac Function. Renal Function and Nitrogen Metabolics. Gastric, Pancreatic, And Intestinal Function. Organ Transplantation. Nutritional Assessment, Therapy, And Monitoring. Mineral and Bone Metabolism. General Endocrine Function. Pituitary Function. Thyroid Function. Function of the Adrenal Cortex. Cathecol Amines and Serotonin. Reproductive Endocrine Function. Biochemical Aspects of Hematology. Porphyrins and Disorders of Porphyrin Metabolism. Clinical Chemistry of Pregnancy. Lysosomal Storage Disease. Appendix.

A SIMPLE PHENYLALANINE METHOD FOR DETECTING PHENYLKETONURIA IN LARGE POPULATIONS OF NEWBORN INFANTS

1963-09-01

Robert Guthrie , Ada Susi

A new method is described for rapid and economical screening of large numbers of hospital nursery infants for elevation in blood phenylalanine associated with phenylketonuria. Results are presented for 682 … A new method is described for rapid and economical screening of large numbers of hospital nursery infants for elevation in blood phenylalanine associated with phenylketonuria. Results are presented for 682 infants, 96% of whom were 4 days of age. None of the blood phenylalanine values were found to be as high as 4 mg/100 ml, and only 8% were above 2 mg/100 ml. These values appear to be in agreement with values obtained by other methods, and indicate that a very low rate of "false-positives" will be encountered during screening of the 10,000 or more infants that may be necessary to detect a case of phenylketonuria. It is recommended that any result of 6 mg/100 ml or above be considered positive, and require confirmation by phenylalanine determination of a second blood specimen.

Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types

1993-03-01

Jutta Urenjak , Stephen R. Williams , DG Gadian +1 more

Proton nuclear magnetic resonance (1H NMR) spectroscopy is a noninvasive technique that can provide information on a wide range of metabolites. Marked abnormalities of 1H NMR brain spectra have been … Proton nuclear magnetic resonance (1H NMR) spectroscopy is a noninvasive technique that can provide information on a wide range of metabolites. Marked abnormalities of 1H NMR brain spectra have been reported in patients with neurological disorders, but their neurochemical implications may be difficult to appreciate because NMR data are obtained from heterogeneous tissue regions composed of several cell populations. The purpose of this study was to examine the 1H NMR profile of major neural cell types. This information may be helpful in understanding the metabolic abnormalities detected by 1H NMR spectroscopy. Extracts of cultured cerebellar granule neurons, cortical astrocytes, oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells, oligodendrocytes, and meningeal cells were analyzed. The purity of the cultured cells was > 95% with all the cell lineages, except for neurons (approximately 90%). Although several constituents (creatine, choline-containing compounds, lactate, acetate, succinate, alanine, glutamate) were ubiquitously detectable with 1H NMR, each cell type had distinctive qualitative and/or quantitative features. Our most unexpected finding was a large amount of N-acetyl-aspartate (NAA) in O-2A progenitors. This compound, consistently detected by 1H NMR in vivo, was previously thought to ne present only in neurons. The finding that meningeal cells have an alanine:creatine ratio three to four times higher than astrocytes, neurons, or oligodendrocytes is in agreement with observations that meningiomas express a higher alanine:creatine ratio than gliomas. The data suggest that each individual cell type has a characteristic metabolic pattern that can be discriminated by 1H NMR, even by looking at only a few metabolites (e.g., NAA, glycine, beta-hydroxybutyrate).(ABSTRACT TRUNCATED AT 250 WORDS)

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The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver

1967-05-01

DH Williamson , P. Kay Lund , HA Krebs

1. The concentrations of the oxidized and reduced substrates of the lactate-, beta-hydroxybutyrate- and glutamate-dehydrogenase systems were measured in rat livers freeze-clamped as soon as possible after death. The substrates … 1. The concentrations of the oxidized and reduced substrates of the lactate-, beta-hydroxybutyrate- and glutamate-dehydrogenase systems were measured in rat livers freeze-clamped as soon as possible after death. The substrates of these dehydrogenases are likely to be in equilibrium with free NAD(+) and NADH, and the ratio of the free dinucleotides can be calculated from the measured concentrations of the substrates and the equilibrium constants (Holzer, Schultz & Lynen, 1956; Bücher & Klingenberg, 1958). The lactate-dehydrogenase system reflects the [NAD(+)]/[NADH] ratio in the cytoplasm, the beta-hydroxybutyrate dehydrogenase that in the mitochondrial cristae and the glutamate dehydrogenase that in the mitochondrial matrix. 2. The equilibrium constants of lactate dehydrogenase (EC 1.1.1.27), beta-hydroxybutyrate dehydrogenase (EC 1.1.1.30) and malate dehydrogenase (EC 1.1.1.37) were redetermined for near-physiological conditions (38 degrees ; I0.25). 3. The mean [NAD(+)]/[NADH] ratio of rat-liver cytoplasm was calculated as 725 (pH7.0) in well-fed rats, 528 in starved rats and 208 in alloxan-diabetic rats. 4. The [NAD(+)]/[NADH] ratio for the mitochondrial matrix and cristae gave virtually identical values in the same metabolic state. This indicates that beta-hydroxybutyrate dehydrogenase and glutamate dehydrogenase share a common pool of dinucleotide. 5. The mean [NAD(+)]/[NADH] ratio within the liver mitochondria of well-fed rats was about 8. It fell to about 5 in starvation and rose to about 10 in alloxan-diabetes. 6. The [NAD(+)]/[NADH] ratios of cytoplasm and mitochondria are thus greatly different and do not necessarily move in parallel when the metabolic state of the liver changes. 7. The ratios found for the free dinucleotides differ greatly from those recorded for the total dinucleotides because much more NADH than NAD(+) is protein-bound. 8. The bearing of these findings on various problems, including the following, is discussed: the number of NAD(+)-NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of the redox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate; the relations between the redox state of cell compartments and ketosis.

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Biochemistry and physiology of brain ammonia.

1987-04-01

Arthur J.L. Cooper , F. Plum

Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine

1977-09-01

Jacob D. Peuler , Garland A. Johnson

THE SUBMITOCHONDRIAL LOCALIZATION OF MONOAMINE OXIDASE

1967-03-01

Carl A. Schnaitman , V. Gene Erwin , John W. Greenawalt

Controlled osmotic lysis (water-washing) of rat liver mitochondria results in a mixed population of small vesicles derived mainly from the outer mitochondrial membrane and of larger bodies containing a few … Controlled osmotic lysis (water-washing) of rat liver mitochondria results in a mixed population of small vesicles derived mainly from the outer mitochondrial membrane and of larger bodies containing a few cristae derived from the inner membrane. These elements have been separated on Ficoll and sucrose gradients. The small vesicles were rich in monoamine oxidase, and the large bodies were rich in cytochrome oxidase. Separation of the inner and outer membranes has also been accomplished by treating mitochondria with digitonin in an isotonic medium and fractionating the treated mitochondria by differential centrifugation. Treatment with low digitonin concentrations released monoamine oxidase activity from low speed mitochondrial pellets, and this release of enzymatic activity was correlated with the loss of the outer membrane as seen in the electron microscope. The low speed mitochondrial pellet contained most of the cytochrome oxidase and malate dehydrogenase activities of the intact mitochondria, while the monoamine oxidase activity could be recovered in the form of small vesicles by high speed centrifugation of the low speed supernatant. The results indicate that monoamine oxidase is found only in the outer mitochondrial membrane and that cytochrome oxidase is found only in the inner membrane. Digitonin treatment released more monoamine oxidase than cytochrome oxidase from sonic particles, thus indicating that digitonin preferentially degrades the outer mitochondrial membrane.

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AN ELECTRON-TRANSPORT SYSTEM ASSOCIATED WITH THE OUTER MEMBRANE OF LIVER MITOCHONDRIA

1967-02-01

Gian Luigi Sottocasa , Bo Kuylenstierna , Lars Ernster +1 more

Preparations of rat-liver mitochondria catalyze the oxidation of exogenous NADH by added cytochrome c or ferricyanide by a reaction that is insensitive to the respiratory chain inhibitors, antimycin A, amytal, … Preparations of rat-liver mitochondria catalyze the oxidation of exogenous NADH by added cytochrome c or ferricyanide by a reaction that is insensitive to the respiratory chain inhibitors, antimycin A, amytal, and rotenone, and is not coupled to phosphorylation. Experiments with tritiated NADH are described which demonstrate that this "external" pathway of NADH oxidation resembles stereochemically the NADH-cytochrome c reductase system of liver microsomes, and differs from the respiratory chain-linked NADH dehydrogenase. Enzyme distributation data are presented which substantiate the conclusion that microsomal contamination cannot account for the rotenone-insensitive NADH-cytochrome c reductase activity observed with the mitochondria. A procedure is developed, based on swelling and shrinking of the mitochondria followed by sonication and density gradient centrifugation, which permits the separation of two particulate subfractions, one containing the bulk of the respiratory chain components, and the other the bulk of the rotenone-insensitive NADH-cytochrome c reductase system. Morphological evidence supports the conclusion that the former subfraction consists of mitochondria devoid of outer membrane, and that the latter represents derivatives of the outer membrane. The data indicate that the electron-transport system associated with the mitochondrial outer membrane involves catalytic components similar to, or identical with, the microsomal NADH-cytochrome b(5) reductase and cytochrome b(5).

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Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: A distinctive clinical syndrome

1984-10-01

Steven G. Pavlakis , Peter C. Phillips∥ , Salvatore DiMauro +2 more

Abstract We report on two patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These two and nine other reported patients share … Abstract We report on two patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These two and nine other reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from two other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns‐Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these three clinical syndromes remain to be elucidated.

On the Enzymatic Determination of Blood Glucose

1960-01-01

By E. Raabo , T. Chr. Terkildsen

(1960). On the Enzymatic Determination of Blood Glucose. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 12, No. 4, pp. 402-407. (1960). On the Enzymatic Determination of Blood Glucose. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 12, No. 4, pp. 402-407.

Online Mendelian Inheritance In Man (OMIM)

2000-01-01

Ada Hamosh , Alan L. Scott , Joanna Amberger +2 more

Online Mendelian Inheritance In Man (OMIM) is a public database of bibliographic information about human genes and genetic disorders. Begun by Dr. Victor McKusick as the authoritative reference Mendelian Inheritance … Online Mendelian Inheritance In Man (OMIM) is a public database of bibliographic information about human genes and genetic disorders. Begun by Dr. Victor McKusick as the authoritative reference Mendelian Inheritance in Man, it is now distributed electronically by the National Center for Biotechnology Information (NCBI). Material in OMIM is derived from the biomedical literature and is written by Dr. McKusick and his colleagues at Johns Hopkins University and elsewhere. Each OMIM entry has a full text summary of a genetic phenotype and/or gene and has copious links to other genetic resources such as DNA and protein sequence, PubMed references, mutation databases, approved gene nomenclature, and more. In addition, NCBI's neighboring feature allows users to identify related articles from PubMed selected on the basis of key words in the OMIM entry. Through its many features, OMIM is increasingly becoming a major gateway for clinicians, students, and basic researchers to the ever-growing literature and resources of human genetics.

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Quantitative Analysis of Urine Vapor and Breath by Gas-Liquid Partition Chromatography

1971-10-01

Linus Pauling , Arthur B. Robinson , Roy Teranishi +1 more

When a human being is placed for several days on a completely defined diet, consisting almost entirely of small molecules that are absorbed from the stomach into the blood, intestinal … When a human being is placed for several days on a completely defined diet, consisting almost entirely of small molecules that are absorbed from the stomach into the blood, intestinal flora disappear because of lack of nutrition. By this technique, the composition of body fluids can be made constant (standard deviation about 10%) after a few days, permitting significant quantitative analyses to be performed. A method of temperature-programmed gas-liquid partition chromatography has been developed for this purpose. It permits the quantitative determination of about 250 substances in a sample of breath, and of about 280 substances in a sample of urine vapor. The technique should be useful in the application of the principles of orthomolecular medicine.

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The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

1997-02-01

Julie McGarry , Nicholas F. Brown

First conceptualized as a mechanism for the mitochondrial transport of long‐chain fatty acids in the early 1960s, the carnitine palmitoyltransferase (CPT) system has since come to be recognized as a … First conceptualized as a mechanism for the mitochondrial transport of long‐chain fatty acids in the early 1960s, the carnitine palmitoyltransferase (CPT) system has since come to be recognized as a pivotal component of fuel homeostasis. This is by virtue of the unique sensitivity of the outer membrane CPT I to the simple molecule, malonyl‐CoA. In addition, both CPT I and the inner membrane enzyme, CPT II, have proved to be loci of inherited defects, some with disastrous consequences. Early efforts using classical approaches to characterize the CPT proteins in terms of structure/function/regulatory relationships gave rise to confusion and protracted debate. By contrast, recent application of molecular biological tools has brought major enlightenment at an exponential pace. Here we review some key developments of the last 20 years that have led to our current understanding of the physiology of the CPT system, the structure of the CPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population.

Robbins and Cotran Pathologic Basis of Disease

2005-02-23

Syed A. Hoda , Rana S. Hoda

1New York Presbyterian Hospital-Weill, Cornell Medical Center, New York, NY 2Medical University of South Carolina, Charleston, SC 1New York Presbyterian Hospital-Weill, Cornell Medical Center, New York, NY 2Medical University of South Carolina, Charleston, SC

A RAPID AND PRECISE METHOD FOR THE DETERMINATION OF UREA

1960-03-01

Janet Fawcett , J. E. Scott

A method is described for the determination of urea in plasma and urine. The effects of variations in the experimental conditions are examined and the results of recovery experiments and … A method is described for the determination of urea in plasma and urine. The effects of variations in the experimental conditions are examined and the results of recovery experiments and other tests of precision and accuracy are reported. In comparison with other methods in current use, this method has distinct advantages in sensitivity, simplicity, and precision, thus economizing in time, sample volume, reagents, and equipment.

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A new enzymatic method for determination of serum choline-containing phospholipids

1977-08-01

Masaharu Takayama , Susumu Itoh , T. Nagasaki +1 more

Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent

1968-01-01

J Sedlák , Robert S. Lindsay

Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies

1988-02-01

Ian Holt , A. E. Harding , J A Morgan-Hughes

Maternal inheritance of human mitochondrial DNA.

1980-11-01

Richard E. Giles , Hugues Blanc , Howard M. Cann +1 more

Human mitochondrial DNA was obtained from peripheral blood platelets donated by the members of several independent families. The samples were screened for nucleotide sequence polymorphisms between individuals within these families. … Human mitochondrial DNA was obtained from peripheral blood platelets donated by the members of several independent families. The samples were screened for nucleotide sequence polymorphisms between individuals within these families. In each family in which we were able to detect a distinctly different restriction endonuclease cleavage pattern between the parents, the progeny exhibited the maternal cleavage pattern. Informative polymorphisms were detected for Hae II (PuGCGCPy) in a three-generation family composed of 33 members, for HincII (GTPyPuAC) in a two-generation family composed of four members, and for Hae III(GGCC) in a two-generation family composed of four members. The Hae II polymorphism was analyzed through all three generations in both the maternal and paternal lines. The results of this study demonstrate that human mitochondrial DNA is maternally inherited. The techniques described for using peripheral blood platelets as a source of human mitochondrial DNA represent a convenient way to obtain data on mitochondrial DNA variation in both individuals and populations.

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Variable Number of Tandem Repeat (VNTR) Markers for Human Gene Mapping

1987-03-27

Yusuke Nakamura , Mark Leppert , P. OʼConnell +7 more

A large collection of good genetic markers is needed to map the genes that cause human genetic diseases. Although nearly 400 polymorphic DNA markers for human chromosomes have been described, … A large collection of good genetic markers is needed to map the genes that cause human genetic diseases. Although nearly 400 polymorphic DNA markers for human chromosomes have been described, the majority have only two alleles and are thus uninformative for analysis of genetic linkage in many families. A few known marker systems, however, detect loci that respond to restriction enzyme cleavage by producing a fragment that can have many different lengths. This polymorphism is due to variation in the number of tandem repeats of a short DNA sequence. Because most individuals will be heterozygous at such loci, these markers will provide linkage information in almost all families. Ten oligomeric sequences derived from the tandem repeat regions of the myoglobin gene, the zeta-globin pseudogene, the insulin gene, and the X-gene region of hepatitis B virus, were used to develop a series of single-copy probes. These probes revealed new, highly polymorphic genetic loci whose allele sizes reflected variation in the number of tandem repeats.

Arginine metabolism and nutrition in growth, health and disease

2008-11-22

Guoyao Wu , Fuller W. Bazer , Teresa A. Davis +7 more

Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain

1970-10-01

Nicolás G. Bazán

Mechanism of Carbon Isotope Fractionation Associated with Lipid Synthesis

1977-07-15

Michael J. DeNiro , Samuel Epstein

The low carbon-13/carbon-12 ratio of lipids is shown to result from isotopic fractionation during the oxidation of pyruvate to acetyl coenzyme A. In vitro analysis of the kinetic isotope effects … The low carbon-13/carbon-12 ratio of lipids is shown to result from isotopic fractionation during the oxidation of pyruvate to acetyl coenzyme A. In vitro analysis of the kinetic isotope effects of this reaction indicates that there will be a large, temperature-dependent difference in the carbon-13/carbon-12 ratio between the methyl and carbonyl carbon atoms of acetyl coenzyme A and between those carbon atoms of lipid components which derive from them.

Carnitine--metabolism and functions

1983-10-01

Jon Bremer

Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. In the … Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. In the last 30 years, interest in the metabolism and functions of carnitine has steadily increased. Carnitine is synthesized in most eucaryotic organisms, although a few insects (and most likely some newborn animals) require it as a nutritional factor (vitamin BT). Carnitine biosynthesis is initiated by methylation of lysine. The trimethyllysine formed is subsequently converted to butyrobetaine in all tissues; the butyrobetaine is finally hydroxylated to carnitine in the liver and, in some animals, in the kidneys (see Fig. 1). It is released from these tissues and is then actively taken up by all other tissues. The turnover of carnitine in the body is slow, and the regulation of its synthesis is still incompletely understood. Microorganisms (e.g., in the intestine) can metabolize carnitine to trimethylamine, dehydrocarnitine (beta-keto-gamma-trimethylaminobutyric acid), betaine, and possibly to trimethylaminoacetone. In some insects carnitine can be converted to methylcholine, presumably with trimethylaminoacetone as an intermediate (see Fig. 3). In mammals the unphysiological isomer (+) carnitine is converted to trimethylaminoacetone. The natural isomer (-)carnitine is excreted unchanged in the urine, and it is still uncertain if it is degraded in mammalian tissues at all (Fig. 2). The only firmly established function of carnitine is its function as a carrier of activated fatty acids and activated acetate across the inner mitochondrial membrane. Two acyl-CoA:carnitine acyltransferases with overlapping chain-length specificities have been isolated: one acetyltransferase taking part in the transport of acetyl and short-chain acyl groups and one palmitoyltransferase taking part in the transport of long-chain acyl groups. An additional octanoyltransferase has been isolated from liver peroxisomes. Although a carnitine translocase that allows carnitine and acylcarnitine to penetrate the inner mitochondrial membrane has been deduced from functional studies (see Fig. 5), this translocase has not been isolated as a protein separate from the acyltransferases. Carnitine acetyltransferase and carnitine octanoyltransferase are also found in the peroxisomes. In these organelles the enzymes may be important in the transfer of acyl groups, which are produced by the peroxisomal beta-oxidation enzymes, to the mitochondria for oxidation in the citric acid cycle. The carnitine-dependent transport of activated fatty acids across the mitochondrial membrane is a regulated process. Malonyl-CoA inh

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Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline

1998-06-15

its Panel on Folate , Other B Vitamins

This report is the second in a series that presents a comprehensive set of reference values for nutrient intakes for healthy U.S and Canadian populations. It is a product of … This report is the second in a series that presents a comprehensive set of reference values for nutrient intakes for healthy U.S and Canadian populations. It is a product of the Food and Nutrition Board of the Institute of Medicine (IOM) working in cooperation with scientists from Canada.The report establishes a set of reference values for the B vitamins and choline to replace previously published Recommended Dietary Allowances (RDAs) for the United States and Recommended Nutrient Intakes (RNIs) for Canada. It considers evidence concerning the prevention of disease and developmental disorders along with more traditional evidence of sufficient nutrient intake; and examines data about choline, a food component that in the past has not been considered essential in the human diet. Although the reference values are based on data, the data were often scanty or drawn from studies that had limitations in addressing the question. Thus, scientific judgment was required in setting the reference values. The reasoning used is described for each nutrient in Chapters 4 through 12. Evidence concerning the use of these nutrients for the amelioration or cure of disease or disability was not considered because that was beyond the project's scope of work.

ANALYTICAL STUDY OF MICROSOMES AND ISOLATED SUBCELLULAR MEMBRANES FROM RAT LIVER

1974-04-01

Henri Beaufay , A Amar-Costesec , Ernest Feytmans +4 more

The series introduced by this paper reports the results of a detailed analysis of the microsomal fraction from rat liver by density gradient centrifugation. The biochemical methods used throughout this … The series introduced by this paper reports the results of a detailed analysis of the microsomal fraction from rat liver by density gradient centrifugation. The biochemical methods used throughout this work for the determination of monoamine oxidase, NADH cytochrome c reductase, NADPH cytochrome c reductase, cytochrome oxidase, catalase, aminopyrine demethylase, cytochromes b(5) and P 450, glucuronyltransferase, galactosyltransferase, esterase, alkaline and acid phosphatases, 5'-nucleotidase, glucose 6-phosphatase, alkaline phosphodiesterase I, N-acetyl-beta-glucosaminidase, beta-glucuronidase, nucleoside diphosphatase, aldolase, fumarase, glutamine synthetase, protein, phospholipid, cholesterol, and RNA are described and justified when necessary.

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Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees.

1993-05-01

Koichiro Tamura , M Nei

Examining the pattern of nucleotide substitution for the control region of mitochondrial DNA (mtDNA) in humans and chimpanzees, we developed a new mathematical method for estimating the number of transitional … Examining the pattern of nucleotide substitution for the control region of mitochondrial DNA (mtDNA) in humans and chimpanzees, we developed a new mathematical method for estimating the number of transitional and transversional substitutions per site, as well as the total number of nucleotide substitutions. In this method, excess transitions, unequal nucleotide frequencies, and variation of substitution rate among different sites are all taken into account. Application of this method to human and chimpanzee data suggested that the transition/transversion ratio for the entire control region was approximately 15 and nearly the same for the two species. The 95% confidence interval of the age of the common ancestral mtDNA was estimated to be 80,000-480,000 years in humans and 0.57-2.72 Myr in common chimpanzees.

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The Acetate Switch

2005-03-01

Alan J. Wolfe

SUMMARY To succeed, many cells must alternate between life-styles that permit rapid growth in the presence of abundant nutrients and ones that enhance survival in the absence of those nutrients. … SUMMARY To succeed, many cells must alternate between life-styles that permit rapid growth in the presence of abundant nutrients and ones that enhance survival in the absence of those nutrients. One such change in life-style, the “acetate switch,” occurs as cells deplete their environment of acetate-producing carbon sources and begin to rely on their ability to scavenge for acetate. This review explains why, when, and how cells excrete or dissimilate acetate. The central components of the “switch” (phosphotransacetylase [PTA], acetate kinase [ACK], and AMP-forming acetyl coenzyme A synthetase [AMP-ACS]) and the behavior of cells that lack these components are introduced. Acetyl phosphate (acetyl∼P), the high-energy intermediate of acetate dissimilation, is discussed, and conditions that influence its intracellular concentration are described. Evidence is provided that acetyl∼P influences cellular processes from organelle biogenesis to cell cycle regulation and from biofilm development to pathogenesis. The merits of each mechanism proposed to explain the interaction of acetyl∼P with two-component signal transduction pathways are addressed. A short list of enzymes that generate acetyl∼P by PTA-ACKA-independent mechanisms is introduced and discussed briefly. Attention is then directed to the mechanisms used by cells to “flip the switch,” the induction and activation of the acetate-scavenging AMP-ACS. First, evidence is presented that nucleoid proteins orchestrate a progression of distinct nucleoprotein complexes to ensure proper transcription of its gene. Next, the way in which cells regulate AMP-ACS activity through reversible acetylation is described. Finally, the “acetate switch” as it exists in selected eubacteria, archaea, and eukaryotes, including humans, is described.

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Automated and Manual Direct Methods for the Determination of Blood Urea

1965-06-01

Walton H. Marsh , Benjamin P. Fingerhut , Henry Miller

Abstract Automated and manual direct methods for the determination of urea in blood or serum are described. These methods determine urea by the colored product formed when urea, in relatively … Abstract Automated and manual direct methods for the determination of urea in blood or serum are described. These methods determine urea by the colored product formed when urea, in relatively weak acid solution, reacts with diacetyl monoxime in the presence of thiosemicarbazide and ferric ion. Results are compared with those obtained by urease conversion of urea to ammonia and measurement of the ammonia by nesslerization.

Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma.

1984-07-01

C Huber , J. R. Batchelor , Dietmar Fuchs +7 more

Neopterin, a compound derived from GTP, represents a precursor molecule of biopterin that is an essential cofactor in neurotransmitter synthesis. We have recently reported that in vivo as well as … Neopterin, a compound derived from GTP, represents a precursor molecule of biopterin that is an essential cofactor in neurotransmitter synthesis. We have recently reported that in vivo as well as in vitro immune responses are accompanied by an increased release of neopterin and that this phenomenon can be used for the biochemical monitoring of diseases accompanied by hyperimmune stimulation. This article deals with the cellular origin and the control of this immune response-associated neopterin release in vitro. Using highly purified or monoclonal cellular reagents we demonstrate that macrophages (M phi) stimulated with supernatants from activated T cells release large amounts of neopterin into culture supernatants. Further experiments involving induction of neopterin release from M phi with various human recombinant interferons (IFNs) or neutralization of the effect of T cell supernatants with various monoclonal anti-IFN antibodies revealed immune IFN as the active principle. It thus appears that a metabolic pathway so far exclusively known in context with the generation of an essential cofactor of neurotransmitter-synthesis during immune responses is also activated in M phi under stringent control by immune IFN-like lymphokines.

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Nuclear Acids In Human Blood Plasma.

1948-02-01

Philipp Mandel , P Métais

[15] Isolation of liver or kidney mitochondria

1967-01-01

Diane Johnson , Henry A. Lardy

A simple ultraviolet spectrophotometric method for the determination of protein.

1956-08-01

William J. Waddell

Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-Aminopteroyl-Glutamic Acid (Aminopterin)

1948-06-03

Sidney Farber , Louis K. Diamond , Robert D. Mercer +2 more

IT IS the purpose of this paper to record the results of clinical and hematologic studies on 5 children with acute leukemia treated by the intramuscular injection of a synthetic … IT IS the purpose of this paper to record the results of clinical and hematologic studies on 5 children with acute leukemia treated by the intramuscular injection of a synthetic compound, 4-aminopteroylglutamic acid (aminopterin). This substance is an antagonist to folic acid regarding the growth of Streptococcus faecalis R. The occurrence of what he interpreted as an "acceleration phenomenon" in the leukemic process as seen in the marrow and viscera of children with acute leukemia treated by the injection of folic acid conjugates1 — pteroyltriglutamic acid (teropterin) and pteroyldiglutamic acid (diopterin) — and an experience gained from studies on folic . . .

Microdetermination of plasma phospholipids by trichloroacetic acid precipitation.

1950-01-01

D.B. Zilversmit , A.K. Davis

Chemistry and Biochemistry of Flavoenzymes

2018-05-04

Franz Müller

The refined three-dimensional structure of glutathione reductase three-dimensional structure of medium-chain acyl-co a dehydrogenase xanthine oxidase, xanthine dehydrogenase, and aldehyde oxidase glutamate synthase assimilatory nitrate reductase d- and l-amino acid … The refined three-dimensional structure of glutathione reductase three-dimensional structure of medium-chain acyl-co a dehydrogenase xanthine oxidase, xanthine dehydrogenase, and aldehyde oxidase glutamate synthase assimilatory nitrate reductase d- and l-amino acid oxidases.

Mammalian Protein Metabolism

1969-01-01

Early Diagenesis

1980-12-31

Robert A. Berner

Molecular cell biology

1987-01-01

Phenylketonuria

2010-10-01

Nenad Blau , Francjan J. van Spronsen , Harvey L. Levy

HCC in MASLD and ALD: Biochemical Pathways, Epidemiology, Diagnosis, and Treatment

2025-06-25

Sheel Patel , Fares Kasem , Dylan Flaherty +1 more | BioChem

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with metabolic-dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease (ALD) emerging as major etiologies. This review explores the epidemiological trends, … Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with metabolic-dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease (ALD) emerging as major etiologies. This review explores the epidemiological trends, pathogenesis, and clinical management of HCC arising from MASH and ALD, highlighting both the shared and distinct mechanisms. MASH-HCC is driven by metabolic dysregulation, including obesity, insulin resistance, and lipotoxicity, with genetic polymorphisms such as PNPLA3 and TM6SF2 playing critical roles in disease progression. ALD-HCC, in contrast, is propelled by the toxic byproducts of ethanol metabolism, including acetaldehyde and reactive oxygen species, which induce chronic inflammation, and fibrosis. Both conditions also involve immune dysregulation, gut dysbiosis, and increased intestinal permeability, contributing to hepatic carcinogenesis. The review emphasizes that, while there is consensus regarding the screening of HCC in cirrhosis patients, there is lack of consensus on screening strategies for non-cirrhotic MASH patients who are also at risk for HCC. This underscores the importance of the early detection of cirrhosis using advanced diagnostic tools such as transient elastography and fibrosis scores. Current therapeutic approaches, ranging from surgical resection, liver transplantation, and locoregional therapies to systemic therapies like immune checkpoint inhibitors, are discussed, with an emphasis on the need for personalized treatment strategies. Finally, the review highlights future research priorities, including the development of novel biomarkers, exploration of the gut–liver axis, and deeper investigation of the interplay between genetic predisposition and environmental factors. By synthesizing these insights, the review aims to inform multidisciplinary approaches to reduce the global burden of MASH- and ALD-related HCC and improve patient outcomes.

Association analysis between circulating methylmalonic acid and cognitive performance: a population-based cross-sectional study

2025-06-25

Chao Wang , Wenwei Guo , Yan Xue +1 more | Frontiers in Neurology

Background Cognitive impairment is one of the common manifestations of abnormal development or dysfunction of the nervous system. Methylmalonic acid (MMA) is a dicarboxylic acid in the propionate metabolism pathway … Background Cognitive impairment is one of the common manifestations of abnormal development or dysfunction of the nervous system. Methylmalonic acid (MMA) is a dicarboxylic acid in the propionate metabolism pathway involving vitamin B12 (B12), it is also one of the commonly used biomarkers in human B12 testing. The relationship between MMA and cognition is not yet fully elucidated. Objective A population-based cross-sectional study was performed to assess the correlation between circulating MMA and cognitive performance. Methods This cross-sectional study finally included 4,464 individuals aged 60 years and older who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 and from 2011 to 2014. In addition to cognitive score [Digit Symbol Substitution Test (DSST)] and circulating MMA levels, covariates included sex, age, race, education, marital status, family poverty-to-income ratio (PIR), BMI, smoking, drinking, serum B12, serum folate, and red blood cell folate. In the statistical analysis, one-way ANOVA, Kruskal–Wallis test, Mann–Whitney U test, and Pearson's chi-squared test were used to compare the differences between different groups. Non-linear relationships were analyzed using a restricted cubic spline model. Pearson and Spearman correlation analyses were used to assess associations. The regression model was conducted using a multiple linear regression model. Results A total of 4,464 participants were finally included, with a mean age of 70.05 years (SD: 7.2), and 2,215 males (49.6%). In Spearman correlation analysis, there was a significant negative correlation between serum MMA levels and cognitive levels (ρ = −0.12, p &lt; 0.001). The results of univariate linear regression analysis showed a very significant negative correlation between square roots (sqrt) of MMA and cognitive scores ( B = −0.47, p &lt; 0.001). It remained a significant negative correlation between the sqrt of MMA and cognitive scores after controlling for the various covariates, with B values of −0.13, −0.13, and −0.14, respectively. The results of the stratified analysis indicated that some covariates may affect the stability of the model. The sensitivity analysis results showed that the correlation between the sqrt of MMA and cognitive scores was no longer statistically significant after adjusting for the covariate homocysteine (HCY), or removing patients with hypertension or chronic kidney disease (CKD). Conclusions In the general population aged 60 and above, there was a significant negative correlation between circulating MMA and cognition, with HCY, hypertension, and CKD identified as important influencing factors.

Management of Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) in Pregnancy

2025-06-24

Matthew A. Shear , Allie LaTray , Irene J. Chang +2 more | Metabolites

Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia/glutaric aciduria type II (GA II), is an inborn error of fatty acid, amino acid, and choline metabolism. The chronic management … Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia/glutaric aciduria type II (GA II), is an inborn error of fatty acid, amino acid, and choline metabolism. The chronic management of MADD involves both dietary fat and protein restriction to reduce the substrates of the dehydrogenases affected, the avoidance of prolonged fasting as in any fat metabolism disorder, and monitoring for potential complications. Due to its rarity, there is little published experience on the management of MADD in pregnancy. Herein, we report the successful management of a pregnancy in a patient with late-onset or type III MADD, with considerations for preconception, antepartum, intrapartum, and postpartum care.

What the intensivist should know about hyperammonemia without liver failure

2025-06-24

Aurélien Gonze , Thibault Gennart , Rozina Ghazali +4 more | Journal of Critical Care

Severe Intrauterine Growth Restriction and Postnatal Growth Failure in a Term Neonate

2025-06-23

| American Academy of Pediatrics eBooks

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Carnitine Deficiency in Chronic Kidney Disease: Pathophysiology, Clinical Implications, and Therapeutic Perspectives

2025-06-23

Yusuke Kaida , Kensei Taguchi , Kei Fukami | Nutrients

Carnitine is essential for the mitochondrial transport of long-chain fatty acids and thus plays a pivotal role in energy metabolism, particularly in metabolically active organs, such as skeletal and cardiac … Carnitine is essential for the mitochondrial transport of long-chain fatty acids and thus plays a pivotal role in energy metabolism, particularly in metabolically active organs, such as skeletal and cardiac muscle. In patients with dialysis, carnitine homeostasis is disrupted because of the reduced synthesis, impaired renal reabsorption, and carnitine loss during extracorporeal procedures. Carnitine deficiency is linked to a wide range of clinical manifestations, including muscle weakness, treatment-resistant anemia, intradialytic hypotension, mental disorder, and cardiovascular disease. This review provides a comprehensive overview of the physiological function of carnitine, elucidates the underlying mechanisms of carnitine deficiency in patients with dialysis, and explores the clinical consequences. Furthermore, the efficacy and limitations of L-carnitine supplementation in clinical practice are discussed based on the current literature. A better understanding of the pathophysiological and clinical relevance of carnitine deficiency may help facilitate personalized therapeutic strategies for patients with kidney diseases.

Nonlinear Associations of Uric Acid and Mitochondrial DNA with Mortality in Critically Ill Patients

2025-06-23

Max Lenz , Robert Zilberszac , Christian Hengstenberg +5 more | Journal of Clinical Medicine

Background: Mitochondrial DNA (mtDNA) has strong pro-inflammatory potential and was found to be associated with mortality in critically ill patients. The purine bases from circulating cell-free DNA, including mtDNA, are … Background: Mitochondrial DNA (mtDNA) has strong pro-inflammatory potential and was found to be associated with mortality in critically ill patients. The purine bases from circulating cell-free DNA, including mtDNA, are catabolised into uric acid, contributing to elevated systemic levels. However, the prognostic value of uric acid in unselected critically ill intensive care unit (ICU) patients remains unclear. We aimed to investigate the association between uric acid levels at admission and 30-day mortality, assess its correlation with mtDNA, and examine prognostic relevance based on the primary cause of admission. Methods: This prospective single-centre study included 226 patients admitted to a tertiary care ICU. Uric acid and mtDNA levels were assessed at admission. Survival analyses were performed in the overall cohort and in subgroups stratified by primary diagnosis. Results: Uric acid showed a U-shaped association with 30-day mortality, with both low and high levels linked to reduced survival. In multivariate analysis, the 4th quartile of uric acid remained associated with adverse outcomes, independent of sex, vasopressors, mechanical ventilation, and creatinine (HR 2.549, 95% CI: 1.310–4.958, p = 0.006). A modest correlation was observed between uric acid and mtDNA (r = 0.214, p = 0.020). However, prognostic relevance varied by diagnosis. While uric acid predicted mortality in patients following cardiac arrest (p = 0.017), mtDNA was found to bear prognostic value in cardiogenic shock and decompensated heart failure (p = 0.009). Conclusions: Uric acid was independently associated with mortality in critically ill patients, with both low and high levels carrying prognostic value. Its predictive capabilities differed from mtDNA but showed partial overlap. However, both markers exhibited varying prognostic performance depending on the primary cause of admission.

Kaempferol improves mitochondrial homeostasis via mitochondrial dynamics and mitophagy in diabetic kidney disease

2025-06-23

Chen Xia , Jiale Zhang , Huixi Chen +4 more | International Immunopharmacology

Mitochondrial homeostasis imbalance plays an important role in the development of diabetic kidney disease (DKD). Kaempferol is a key bioactive compound widely present in the rhizomes of Kaempferia L. and … Mitochondrial homeostasis imbalance plays an important role in the development of diabetic kidney disease (DKD). Kaempferol is a key bioactive compound widely present in the rhizomes of Kaempferia L. and vegetables. Its anti-inflammatory and antioxidant properties have gained increasing attention in treating various metabolic diseases. This study investigated whether kaempferol could improve mitochondrial structure and function by regulating mitochondrial dynamics and mitophagy in DKD. A DKD rat model was established via unilateral nephrectomy and streptozotocin injection. Renal function, histopathology, and inflammatory factors were assessed, along with fibrosis, apoptosis, mitochondrial dynamics, and mitophagy-related proteins. Meanwhile, an AGEs-induced HK-2 cell injury model was used to evaluate autophagic flux and mitochondrial function and morphology through ad-mCherry-GFP-LC3B transduction, JC-1 staining, and MitoTracker probes. In vivo results showed that kaempferol exhibited significant anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in DKD rats. Moreover, kaempferol demonstrated good safety by alleviating hepatic fibrosis. It also restored mitochondrial dynamics by promoting the upregulation of mitochondrial fusion proteins (Mfn1, OPA1) and the downregulation of fission proteins (Drp1, Fis1). In addition, kaempferol enhanced mitochondrial biogenesis by upregulating PGC-1α and TFAM. Notably, kaempferol reactivated mitophagy, as evidenced by increased levels of PINK1, Parkin, LC3, Beclin1, and ATG5, along with a reduction in p62 levels. In vitro, kaempferol further demonstrated its antioxidative potential by increasing SOD levels and decreasing MDA levels. Additionally, it promoted autophagic induction and facilitated the fusion of autophagosomes with lysosomes. These combined effects led to the restoration of mitochondrial membrane potential and structural integrity, while reducing ROS production and enhancing ATP generation. In conclusion, kaempferol promotes mitochondrial fusion, restores mitophagy, enhances autophagy flux, and facilitates mitochondrial clearance, showing the potential to mitigate kidney injury and slow disease progression in DKD.

Altered Mental Status in a 5-year-old Girl

2025-06-23

| American Academy of Pediatrics eBooks

dd-cfDNA Interpretation: Same Sample, Different Story?

2025-06-23

Changhong Xu , Yun Deng , Jiangwei Man +2 more | Transplantation

Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy

2025-06-22

Yi Wen , Xiaozhu Ma , Shuai Mei +2 more | Biomolecules

Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and … Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and 2 diabetes and is fundamentally characterized by abnormalities in myocardial structure and function. Metabolic disorders occupy a leading role in the pathogenesis of DCM, manifesting as disrupted substrate metabolism, dysregulated signaling pathways, and energy imbalance. Given the limited benefits of conventional therapeutic strategies targeting glucolipid metabolism, increasing research efforts have focused on amino acid metabolism. Amino acids are involved in the synthesis of nitrogen-containing compounds and serve as an energy source under specific conditions. Moreover, emerging studies demonstrate that metabolic disturbances of specific amino acids—such as branched-chain amino acids (BCAAs), glutamine, and arginine—exacerbate mitochondrial dysfunction and oxidative stress, thereby promoting myocardial fibrosis and cardiomyocyte injury. Therefore, this review aims to summarize the general characteristics and regulatory pathways of amino acid metabolism, as well as the specific mechanisms by which metabolic alterations of amino acids contribute to the pathogenesis and progression of diabetic cardiomyopathy, with the hope of advancing more effective translational therapeutic approaches.

<scp>HMG</scp>‐<scp>CoA</scp> Synthase‐2 Deficiency: Neonatal Hyperammonemic Coma and Abnormal Metabolic Screening Resembling Maple Syrup Urine Disease

2025-06-22

Hathaipat Vaseenon , Thipwimol Tim‐Aroon , Vitchayaporn Emarach Saengow +4 more | JIMD Reports

Mitochondrial HMG-CoA synthase-2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. … Mitochondrial HMG-CoA synthase-2 (HMGCS2) deficiency is characterized by hypoketotic hypoglycemia, metabolic acidosis, hepatomegaly, and encephalopathy with onset between 3 and 36 months of age. Approximately 50 cases were reported worldwide. We describe two patients with HMGCS2 deficiency. Patient 1 presented on day of life 7 with a sepsis-like condition, coma, metabolic acidosis, and marked elevation of ammonium level at 1081 μmol/L. Metabolic screening demonstrated elevated valine and leucine/isoleucine concentrations, resembling maple syrup urine disease (MSUD). The patient received a blood exchange transfusion, which lowered the ammonium level to 92 μmol/L. Urine organic acid analysis did not confirm MSUD. At 1 year and 4 months, the patient experienced acute decompensation again. Exome sequencing revealed a homozygous HMGCS2 variant, c.1502G>C (p.Arg501Pro). Patient 2, an older sibling of Patient 1, was healthy but diagnosed through genetic testing. Both patients exhibited abnormal biochemical profiles, including dicarboxylic aciduria and increased urinary excretion of 4-hydroxy-6-methyl-2-pyrone (4-HMP) after 8 h of fasting, suggesting that a clinically asymptomatic patient, like Patient 2, may eventually develop acute decompensation. Therefore, preemptive treatment with fasting avoidance with or without l-carnitine during intercurrent illness should be advised. The present cases were the second and third patients of p.Arg501Pro homozygosity. The elevated branched-chain amino acids in the metabolic screening (without including alloisoleucine) and the described organic acid profile can be found during the catabolic state, resembling MSUD, and severe hyperammonemia is an uncommon phenotype and an exception to neonatal decompensation in HMGCS2 deficiency. Our findings demonstrated intrafamilial variability and expanded the clinical and biochemical spectrum of HMGCS2 deficiency.

Adenosine

2025-06-21

| Reactions Weekly

Sideroflexins enable mitochondrial transport of polar neutral amino acids

2025-06-21

Samuel Block , Fangtao Chi , Paul C. Rosen +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Mitochondria contribute to compartmentalized metabolism in eukaryotic cells, supporting key enzymatic reactions for cell function and energy homeostasis. However, this compartmentalization necessitates regulated metabolite transport across mitochondrial membranes. Although many … Mitochondria contribute to compartmentalized metabolism in eukaryotic cells, supporting key enzymatic reactions for cell function and energy homeostasis. However, this compartmentalization necessitates regulated metabolite transport across mitochondrial membranes. Although many transport proteins have been identified, several mitochondrial amino acid transporters remain largely uncharacterized. Using CRISPR-Cas9-mediated candidate transporter knockouts coupled with assessment of metabolite transport via a mitochondrial swelling assay, we identify SFXN1, previously characterized for its role in mitochondrial serine transport, as a protein that mediates mitochondrial transport of a range of other polar neutral amino acids including proline, glycine, threonine, taurine, hypotaurine, β-alanine, and γ-aminobutyric acid (GABA). Furthermore, the SFXN1 paralogues SFXN2 and SFXN3 partially complement loss of SFXN1 to enable glycine transport, while SFXN2 and SFXN5 partially complement loss of SFXN1 to enable GABA transport. Altogether, these data suggest that sideroflexins facilitate the transport of polar neutral amino acids across the inner mitochondrial membrane.

Levetiracetam

2025-06-21

| Reactions Weekly

Update of the sideroflexin (SLC56) gene family

2025-06-20

Angeliki I. Katsafadou , Daniel W. Nebert , Sergey A. Krupenko +2 more | Human Genomics

The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, … The human sideroflexin (SFXN) gene family, also classified as solute carrier family 56 (SLC56), encodes a group of five mitochondrial transmembrane proteins (SFXN1-SFXN5) involved in key aspects of mitochondrial metabolism, cellular homeostasis, and development. SFXNs are highly conserved across eukaryotic species, with evolutionary the origin traced back to the earliest metazoans. Functionally, each of the five family members exhibits distinct functional specialization. Particularly, SFXN1 and SFXN3 facilitate mitochondrial serine transport, supporting one-carbon metabolism. SFXN2 and SFXN4 are implicated in mitochondrial iron regulation, heme biosynthesis, and iron-sulfur cluster assembly. SFXN5, predominantly expressed in the brain, is proposed to regulate citrate metabolism and immune cell functions. Mutations or dysregulation of SFXN genes have been linked to certain human diseases, including congenital sideroblastic anemia, oxidative phosphorylation disorders, neurodegenerative conditions, and cancers. Structurally, SFXNs share conserved transmembrane domains and key motifs critical for substrate transport, mitochondrial iron homeostasis, and overall mitochondrial function. The evolutionary trajectory of the SFXN family-from amino acid transport to functionally specialized roles in higher organisms-highlights their biological and clinical significance. Comparative studies across model organisms reveal both conserved and divergent functions, emphasizing their importance in health and disease. A comprehensive understanding of the SFXN family not only advances fundamental mitochondrial research but also opens avenues for novel therapeutic interventions.

Glufosinate-ammonium poisoning: A clinical case

2025-06-20

Jun Luo , L. Kong , Yuanyuan Kuang | Medicina Clínica

Treatment of Ochronotic Osteoarthropathy and the Evaluation of Selected Lower Limb Muscle Properties, Including the Patellar Tendon: A Case Report and Mini Literature Review

2025-06-20

Jaromir Jarecki , Agnieszka Tomczyk‐Warunek , Agnieszka Posturzyńska +7 more | Journal of Clinical Medicine

Background/Objectives: Alkaptonuria (AKU) is a rare genetic disorder characterized by elevated levels of circulating homogentisic acid (HGA), which accumulates in connective tissues. The musculoskeletal system is particularly susceptible to HGA … Background/Objectives: Alkaptonuria (AKU) is a rare genetic disorder characterized by elevated levels of circulating homogentisic acid (HGA), which accumulates in connective tissues. The musculoskeletal system is particularly susceptible to HGA deposition, often resulting in severe ochronotic osteoarthropathy, especially in the hips, shoulders, knees, and spine. However, little is known about the effects of AKU on skeletal muscle tissue. The study aimed to evaluate changes in lower limb muscles associated with AKU. Methods: This case report describes the treatment of ochronotic osteoarthropathy in the knee of a 73-year-old male patient. Muscle properties were assessed using the MyotonPRO device. The rectus femoris, vastus medialis, and patellar tendon were examined both preoperatively and three months postoperatively. Results: Following total knee arthroplasty (TKA) of the right knee, the patient demonstrated significant improvement in functional outcomes. The MyotonPRO assessment revealed measurable differences in muscle properties between the operated and non-operated limbs. Postoperative measurements indicated improvements in muscle tone, elasticity, and viscoelastic parameters in the treated limb. Conclusions: This case report supports the effectiveness of TKA as a treatment for ochronotic osteoarthropathy. Furthermore, it is the first study to use the MyotonPRO to assess muscle and tendon properties in a patient with AKU. These findings highlight the need for further research into the muscular effects of this rare metabolic disorder.

Intelligence quotient scores among early-treated phenylketonuria patients: results from a systematic literature review

2025-06-20

Fiona O’Sullivan , Ioannis Tomazos , Francjan J. van Spronsen +7 more | Orphanet Journal of Rare Diseases

Abstract Background Phenylketonuria (PKU) is a rare condition that causes the accumulation of phenylalanine; without prompt diagnosis and treatment following birth, severe neurologic and cognitive impairments occur. While dietary management … Abstract Background Phenylketonuria (PKU) is a rare condition that causes the accumulation of phenylalanine; without prompt diagnosis and treatment following birth, severe neurologic and cognitive impairments occur. While dietary management can help reduce Phe levels, adherence is challenging and deficits in cognitive function often remain. The importance of the exact features of dietary management, treatment, and control at different time points with respect to eventual IQ scores has not been established. The objective of the present study was to review and describe published data on the impact of PKU on cognition as measured by IQ among PKU patients receiving early dietary management. Methods A systematic literature review was conducted following PRISMA guidelines to examine IQ among patients with PKU. Instruments used to assess IQ included the Wechsler Intelligence Scale, Culture Fair Intelligence Test and Stanford Binet Test. Results were reported overall and by subgroups. Results Twenty-five out of 28 identified studies could be included in the review. Lower IQ scores were generally observed among those with high phenylalanine levels, although variations in the study populations hinder the ability to make comparisons. Mean IQ scores among those with PKU were consistently lower compared to control groups. Even though all patients in this review received early treatment, those with poor dietary adherence and higher phenylalanine levels tended to show poorer cognitive ability. Conclusions Cognition is affected in PKU, despite early and continuous dietary management. Treatments are needed that reduce phenylalanine levels so that the burden of neurocognitive impairment in PKU can be alleviated.

Rethinking phenylalanine levels in phenylketonuria for optimal neurocognitive development beyond childhood

2025-06-19

Beatriz Câmara , Cristina Florindo , Cláudia Bandeira de Lima +5 more | Frontiers in Pediatrics

Introduction Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that disrupts neurotransmitter balance. Although early intervention has improved outcomes, neurocognitive challenges persist, particularly during adolescence. Metabolic control guidelines … Introduction Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that disrupts neurotransmitter balance. Although early intervention has improved outcomes, neurocognitive challenges persist, particularly during adolescence. Metabolic control guidelines for patients aged &gt;12 years differ between the European Union and the United States, with recommended blood Phe levels below 600 µM and 360 µM, respectively. Methods This study evaluated the relationship between blood Phe levels, intelligence quotient (IQ), and executive functions using the Wechsler Intelligence Scale for Children-Third Edition and the d2 Test of Attention. Blood Phe levels were monitored longitudinally and summarized using the Index of Dietary Control (IDC), calculated as the mean of individual annual median Phe concentrations, both before and after 12 years of age. Results The study included 14 early-treated PKU patients aged 12–17 years, all diagnosed through newborn screening programs. Participants maintained good metabolic control (IDC &lt;360 µM) prior to 12 years of age, with a mean IDC of 302 µM. Higher IQ scores before the age of 12 years were observed only among patients with consistent dietary compliance. After that age, attentional performance declined in those who were noncompliant with dietary recommendations. Additionally, occasional elevations in blood Phe levels at the time of cognitive assessments were associated with poorer cognitive performance. Discussion These findings underscore the detrimental effects of elevated Phe levels on executive functions during adolescence and highlight the need for larger studies to determine whether blood Phe levels between 360 and 600 µM are safe for patients aged &gt;12 years.

Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type

2025-06-19

Lili Hao , Yuxin Deng , Si Ding +7 more | Molecular Genetics and Metabolism

Delayed Diagnosis of Glutaric Aciduria Type 1: A Case Report

2025-06-19

Cesar Esteban Larancuent , Tracey Weiler , Sajel L Kana | Cureus

Assessment and Application of Acylcarnitines Summations as Auxiliary Quantization Indicator for Primary Carnitine Deficiency

2025-06-19

Huang Zhi , Siyu Chang , Ting Chen +5 more | International Journal of Neonatal Screening

Newborns are referred primary carnitine deficiency (PCD) when a low free carnitine (C0) concentration (<10 μmol/L) is detected, leading to high false-positive referrals. To improve the follow-up protocol for PCD, … Newborns are referred primary carnitine deficiency (PCD) when a low free carnitine (C0) concentration (<10 μmol/L) is detected, leading to high false-positive referrals. To improve the follow-up protocol for PCD, various acylcarnitines and the summations were comprehensively evaluated in the present study. A retrospective study was performed using samples due to low C0 concentration. Data were available for 72 patients with genetically confirmed PCD, whereafter C0 with the selected sum of (butyrylcarnitine (C4) + isovalerylcarnitine (C5)) was validated in an additional cohort study including about 80,000 samples. In the discovery study, C4, acetylcarnitine (C2) and C5 exhibited significant discriminant power in distinguishing PCDs from NoPCDs. The area under the ROC curve (AUC) was 99.792% (C4), 98.715% (C2) and 98.620% (C5). The excellent performances in sensitivity, specificity, negative predictive value, positive predictive value (PPV) and accuracy indexes suggested that C4, C2 and C5 would be ideal auxiliary indicators in improving the diagnostic performance of C0 for PCD. Multivariate ROC curve-based exploratory analysis showed that C5, C4 and C2 were the most top-ranked features in differentiating PCDs from NoPCDs. AUC for C4 + C5 was the highest with a cutoff required for 100% sensitivity at 0.181 μmol/L. In the validation cohort, adding C4 + C5 in the NBS program could elevate PPV from 0.75% to 1.54%. Our work revealed that C4 + C5 summation should be used as the auxiliary quantization indicator to reduce false-positive results for PCD.

Levothyroxine Requirement in a Patient with LRBA Deficiency and GVHD Induced Cholestasis

2025-06-19

Yusriya Al Rawahi , Hussain Alsaffar , Abdelmohaymin Abdalla +1 more | Sultan Qaboos University medical journal

A Case of Alkaptonuria: Unexplained Arthropathy, Urine Discoloration, and the Importance of Metabolic Clues in Rare Diagnoses

2025-06-19

Saba Afreen | International Journal of Contemporary Medicine

IntroductionAlkaptonuria is a rare autosomal recessive metabolic disorder caused by homogentisate 1,2-dioxygenase (HGD) deficiency, leading to the accumulation of homogentisic acid (HGA). This condition manifests through dark urine, progressive ochronosis … IntroductionAlkaptonuria is a rare autosomal recessive metabolic disorder caused by homogentisate 1,2-dioxygenase (HGD) deficiency, leading to the accumulation of homogentisic acid (HGA). This condition manifests through dark urine, progressive ochronosis (tissue pigmentation), early-onset arthritis, and may include cardiovascular complications.This case highlights the importance of considering metabolic etiologies in early degenerative joint disease, particularly when accompanied by systemic signs like urine discoloration and scleral pigmentation. It adds to scientific literature by reaffirming that rare diseases can present even in under-resourced settings and require clinical vigilance for early diagnosis and intervention. Patient Concerns and Key Clinical FindingsA young adult male presented with:Urinary changes: Darkening of urine upon standing.Ochronosis:Bluish-black pigmentation of scleraPigmentation of ear cartilage and skin foldsOchronotic arthropathy:Progressive joint pain and stiffnessAffected areas: thoracolumbar and lumbosacral spine, large joints (knees, hips)X-rays revealed: intervertebral disc calcification, joint space narrowingCardiovascular involvement:Evidence of aortic valve calcification on echocardiography DiagnosisClinical Clues:Progressive early-onset arthropathyUrine discolorationVisible pigmentation (ochronosis)Laboratory Findings:Ferric chloride test: Black colorationBenedict’s test: Green to black precipitateGas chromatography–mass spectrometry (GC-MS): Elevated homogentisic acid (HGA)Genetic testing: Mutation in HGD gene confirmed diagnosis Interventions1. Symptomatic Management:NSAIDs for joint pain and stiffnessPhysiotherapy to preserve joint mobility2. Dietary and Medical Support:Low-protein diet to reduce phenylalanine and tyrosine intake (precursors of HGA)Vitamin C supplementation to slow oxidative polymerization of HGA3. Monitoring and Surveillance:Serial imaging to monitor spinal and joint degenerationRegular urinalysis for metabolic monitoring4. Genetic Counseling:Family screening and education about autosomal recessive inheritanceCarrier testing for first-degree relatives5. Orthopedic Referral:For early assessment and management of degenerative joint changes OutcomesAt 3-month follow-up:Joint symptoms moderately improved with NSAIDs and physiotherapyUrine discoloration persistedPatient reported better functional capacity in daily activitiesAdherence to lifestyle and diet modifications was satisfactory Conclusion and Key TakeawaysThink metabolic in unexplained early-onset arthritis—especially when accompanied by systemic clues.Urine discoloration is a simple but underrecognized diagnostic sign of alkaptonuria.Ochronosis, though delayed, is a diagnostic hallmark.Early diagnosis and multidisciplinary care can improve quality of life and delay joint deterioration.Rare diseases occur even in rural or peripheral health settings, emphasizing the need for awareness and basic metabolic workups in atypical arthropathy cases.

Lactancia materna exclusiva ¿Por qué debe ser supervisada?

2025-06-18

CARLOS LOPEZ CANDIANI | Acta Pediátrica de México

El alimento natural para el recién nacido es la leche de su propia madre, la cual ofrece nutrición personalizada y beneficios inmunológicos y psicológicos para el óptimo desarrollo físico y … El alimento natural para el recién nacido es la leche de su propia madre, la cual ofrece nutrición personalizada y beneficios inmunológicos y psicológicos para el óptimo desarrollo físico y mental. Sin embargo, en situaciones particulares, puede asociarse a eventos no deseados en el lactante, por lo que debe ser supervisada médicamente. El objetivo del presente artículo es revisar los posibles desenlaces adversos en lactantes exclusivamente amamantados que no han tenido la supervisión médica adecuada. Se hacen recomendaciones para evitar deshidratación, hipernatremia, ictericia intensa y otros eventos asociados a lactancia exclusiva.

The difference of variation types between late-onset multiple acyl-CoA dehydrogenase deficiency patients carrying biallelic and single heterozygous variations in ETFDH: a systematic review and meta-analysis

2025-06-18

Huiqiu Zhang , Jing Ma , Menghan Su +7 more | Orphanet Journal of Rare Diseases

Abstract Background Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disease chiefly caused by mutations in ETFDH gene. Mutations in the ETFDH gene lead to abnormal structure, impaired … Abstract Background Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disease chiefly caused by mutations in ETFDH gene. Mutations in the ETFDH gene lead to abnormal structure, impaired function, and increased degradation of ETFDH protein. However, it is not known why approximately 10% of patients carry single heterozygous variants in ETFDH . We speculate that different variation types (e.g., null variants and missense variants) partially account for the phenomenon. Methods In this study, six databases were searched up until December 01, 2024. Studies describing late-onset MADD patients carrying ETFDH variations were included. The analyses focused on the differences in variation types, computational pathogenicity scores of missense variants, and clinical characteristics between patients with biallelic and single heterozygous variations (biallelic group vs heterozygous group). Results Of the initially screened 3638 studies, 30 met the inclusion criteria, including 498 late-onset MADD patients with biallelic variations and 62 with single heterozygous variations in ETFDH . The relative frequency of patients carrying null variants was lower in the biallelic group (21%, 95% CI [16%-27%]) than that in the heterozygous group (34%, 95% CI [23%-48%]) ( P = 0.044). Missense variants in the heterozygous group had stronger pathogenicity than those in the biallelic group, as reflected by the computational prediction tools, SIFT, PolyPhen-2 and metaRNN ( P < 0.05). Patients carrying biallelic variations had a younger onset age and a higher level of serum creatine kinase at diagnosis ( P < 0.05). Conclusions Late-onset MADD patients carrying single heterozygous variations in ETFDH gene have distinct variation profiles and clinical severity compared to those harboring biallelic variations, which highlights the complexity of this disease.

Materials of the Expert Council “Ornithine in Oncological Practice”

2025-06-18

S. V. Okovityi , M. Yu. Nadinskaia , М. V. Maevskaya +7 more | Meditsinskiy sovet = Medical Council

Among chemotherapy-related adverse events, drug-induced liver injury (DILI) is one of the most prevalent. In some cases, DILI is accompanied by hyperammonaemia (HA), which can disrupt chemotherapy cycles, and is … Among chemotherapy-related adverse events, drug-induced liver injury (DILI) is one of the most prevalent. In some cases, DILI is accompanied by hyperammonaemia (HA), which can disrupt chemotherapy cycles, and is associated with 25–45% mortality rates when specific antitumor agents are used. Efficacy studies in cancer patients were only found for ornithine (L-ornithine L-aspartate, LOLA) among all ammonia-lowering strategies. The amino acids in LOLA help to detoxify ammonia in the liver and other tissues, while also having several other metabolic effects. The experts expressed their viewpoints on the conducted studies, reviewed the main directions for applying LOLA in current clinical practice, and identified prospects for further research.

When the Cure Hurts: Pyridoxine Induced Neuropathy in A Patient Treated for Tuberculosis—A Case Report

2025-06-17

Neeraj Sharma , Robin Chaudhary , Vivek Sharda +1 more | SN Comprehensive Clinical Medicine

Double hypopyon

2025-06-17

Supriya Sharma , Mohammed Saleh Al Ansari , Rupak Roy | Eye

Correction to: Newborn Screening Followed By Early Treatment is Essential to Improve Survival in SCID

2025-06-16

Gabriela Assunção Goebel , Luciana Araújo Oliveira Cunha , Fernanda Gontijo Minafra +1 more | Journal of Clinical Immunology

Structural characterization of the urea transporter bound to the orally bioavailable inhibitor E3

2025-06-16

Shen-Ming Huang , Bo-Yang Cai , Lei Liu +7 more | Acta Pharmacologica Sinica

Total Joint Arthroplasty in Ochronotic Arthritis of Lower Extremities

2025-06-16

Praveen L. Basanagoudar , Dr. MD. Furquan Inamdar , Radhika Devi B +1 more | Indian Journal of Orthopaedics

Ex Vivo Osteoclastogenesis from Peripheral Blood Mononuclear Cells Is Unchanged in Adults with Phenylketonuria, Regardless of Dietary Compliance

2025-06-16

Beatrice Hanusch , Anne Schlegtendal , Thomas Luecke +1 more | International Journal of Molecular Sciences

Pathogenic variants in the phenylalanine hydroxylase gene can result in phenylalanine (Phe) accumulation leading to phenylketonuria (PKU; OMIM #261600), a metabolic disease diagnosed in newborn screening. Early treatment with a … Pathogenic variants in the phenylalanine hydroxylase gene can result in phenylalanine (Phe) accumulation leading to phenylketonuria (PKU; OMIM #261600), a metabolic disease diagnosed in newborn screening. Early treatment with a Phe-restricted diet prevents severe mental retardation. Next to several other health complaints, patients with PKU present with low bone mineral density (BMD) more often than the general population. The etiology of the phenotype is not yet fully understood, and current research focuses on improving special medical foods and changes in osteoclasts (OC) and osteoblasts. Analysis of osteoclastic and oxidative stress control gene expression next to the simple number of OC developing from peripheral blood mononucleated cells (PBMCs) in association with dietary compliance and BMD was therefore part of our analysis. PBMCs were obtained from 17 adults with PKU and 17 age- and sex-matched controls on the same day. PBMCs were differentiated into osteoclasts (OC, Trap-positive multi-nucleated cells (≥3 nuclei)) for 14 days by adding human macrophage colony-stimulating factor (MCSF) and receptor activator of NF-κB Ligand (RANKL). Subsequently, quantitative real-time PCR was performed on OC function and oxidative stress control. Data on dietary compliance during the previous 12 months and 5 years and BMD were collected. PBMCs from adults with PKU and controls were differentiated into comparable numbers of OC (PKU: 53 [17-87] vs. controls: 39 [19-52], p = 0.381) without differences in mRNA expression of genes related to OC function and oxidative stress control. Dietary compliance in short-term and mid-term was not associated with OC number or mRNA expression, but CTSK negatively correlated with BMD T-Score in the hips of adults with PKU (Spearman r = -0.518, p = 0.040). Osteoclastogenesis was not changed in adult patients with PKU, nor were most mRNA expressions of OC marker genes or those of oxidative stress control. However, 44% of patients presented with BMD below -1 in their hips, and the OC of these tended to express higher CTSK (above -1: 0.2 [0.2-0.8] vs. below -1: 0.9 [0.6-3.4], p = 0.055). Thus, alternative regulatory mechanisms of OC activity may play a role in the development of low BMD in patients with PKU.

Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy

2025-06-16

José Manuel Romero-Domínguez , Paula Cilleros-Holgado , Salvador Ibáñez‐Micó +7 more | Antioxidants

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE … Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants.

Erratum to “Dihydropteridine reductase deficiency: The first Moroccan case report” [Brain Dev. Case Rep. 2(2) (2024) 100008]

2025-06-16

Kaoutar Khabbache , Afaf Lamzouri , Hanaa Imlahi +1 more | Brain and Development Case Reports

Association of medium-chain acyl-CoA dehydrogenase with the risk of diabetic kidney disease: a mendelian randomized study

2025-06-16

Haodi Cao , Yaxin An , Yan Ma | HORMONES

Anesthetic management of a child with aromatic L-amino acid decarboxylase deficiency: A case report

2025-06-16

Rayan Muawad , Abdullah AlDhuwaihy , Amani Alghamdi +1 more | Saudi Journal of Anaesthesia

This report discusses the anesthetic management of a 7-year-old child with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare neurometabolic disorder. The patient underwent ventilation tube insertion and adenotonsillectomy. Similar … This report discusses the anesthetic management of a 7-year-old child with aromatic L-amino acid decarboxylase (AADC) deficiency, a rare neurometabolic disorder. The patient underwent ventilation tube insertion and adenotonsillectomy. Similar to other adenotonsillectomy procedures, this surgery carries a higher risk of postoperative nausea and vomiting, necessitating a careful management strategy. We opted for dexamethasone as the primary antiemetic agent and limited opioid use to a single dose of fentanyl, while also incorporating dexmedetomidine for enhanced pain management alongside ketorolac and paracetamol. This case highlights the need for specialized anesthesia protocols for AADC deficiency patients to enhance safety and outcomes, particularly addressing the challenges of nausea and vomiting.

Long Term Follow up of Short-Chain-L-3-Hydroxyacyl-CoA Dehydrogenase (SCHAD) Deficiency Causing Hypoglycemia and Developmental Delays in Two Syrian Brothers

2025-06-16

Annie Li , Robert Stein , C. Anthony Rupar +1 more | The Indian Journal of Pediatrics

Signs of Premature Kidney Aging in Mice With Error‐Prone Protein Synthesis

2025-06-14

Leda Hanel Lang , Rocío Fuente , José M. López +7 more | The FASEB Journal

ABSTRACT Chronic kidney disease (CKD) is more prevalent with increasing age. The incidence of CKD is rising due to the widespread nature of its risk factors, hypertension and diabetes, and … ABSTRACT Chronic kidney disease (CKD) is more prevalent with increasing age. The incidence of CKD is rising due to the widespread nature of its risk factors, hypertension and diabetes, and because aging causes a gradual decline in kidney function. This decline is a consequence of structural, molecular, and metabolic changes occurring in aging kidneys. Understanding the mechanisms that accelerate kidney aging may help manage CKD and promote healthy aging. Recently, it has been shown that protein translation errors accelerate aging in mammals. Mice heterozygous for the ribosomal ambiguity mutation Rps9 D95N , which results in genome‐wide error‐prone translation, have reduced life span, increased macroscopic signs of aging, and exhibit a neuropathological phenotype resembling early signs of Alzheimer disease. Here, using deep phenotyping, we investigated the kidneys of Rps9 D95N/+ mice and showed that genome‐wide error‐prone translation is also associated with signs of premature kidney aging. These mice have renal amyloidosis, an altered glomerular basement membrane, reduced autophagy in kidney tissue, and renal fibrosis compared to age‐matched aged mice. These alterations in kidney tissue were accompanied by signs of kidney dysfunction such as albuminuria and elevated levels of Kim‐1, a marker of kidney injury and kidney disease progression. In addition, lipid metabolism is altered, as shown by RNAseq and targeted metabolomic analysis, suggesting increased lipid deposition as lipid droplets in the Rps9 D95N knock‐in mice. Only mild changes in systemic phosphate metabolism were observed. Our findings provide insights into premature kidney aging, likely due to accelerated loss of proteostasis caused by genome‐wide translation errors.

Low excretor glutaric acidemia type 1 with transient lesions in the basal ganglia

2025-06-14

Yohane Miyata , Kei Murayama , Yasushi Okazaki +3 more | Brain and Development

Self-amplifying mRNA expression is governed by mitochondrial machinery and ACSL4

2025-06-14

Lara F. Tshering , Chong Wang , Qing Xiang +5 more | bioRxiv (Cold Spring Harbor Laboratory)

RNA-based vaccines offer a superior efficacious and economic approach over traditional vaccines. However, current dose requirement and short half-life of conventional modified mRNA (modRNA) may hinder the development of more … RNA-based vaccines offer a superior efficacious and economic approach over traditional vaccines. However, current dose requirement and short half-life of conventional modified mRNA (modRNA) may hinder the development of more effective vaccines. Self-amplifying mRNA (saRNA) is a modality that has the potential to address these limitations by reducing delivery dosage and enhancing the duration of expression over modRNA. Despite marked success in preclinical studies, saRNA vaccines have thus far underperformed in most clinical trials. We hypothesized that non-optimal human cellular context limits saRNA expression, and that elucidating the factors underlying saRNA expression would be key in developing saRNA as a viable therapeutic modality. To identify factors involved in the regulation of saRNA, we performed a quasi-genome-wide CRISPR knockout screen, which revealed that saRNA expression in human cells is linked to mitochondrial function and governed by ACSL4. We validated these findings through pharmacological intervention and single gene editing, demonstrating that ACSL4-mediated regulation is unique to saRNA and does not impact modRNA. Moreover, we show that modulating ACSL4 leads to improved saRNA expression across multiple cell types. We demonstrate for the first time that mitochondrial function and ACSL4 play key roles in saRNA expression, providing insight for the development and implementation of saRNA as a therapeutic modality.

Effects of L-carnitine over-supplementation on spermatogenesis and sperm function in healthy NMRI mice

2025-06-14

Mitra Jabarineitapeh , Nushin Naderi , Marziyeh Tavalaee +1 more | Tissue and Cell

A case report of combined methylmalonic acidemia and homocysteinemia presented with cerebral sinus thrombosis and fluctuating cognitive impairment

2025-06-13

Jingshi Wang , Lu Liu , Huiting Wang | Medicine

Rationale: MMACHC deficiency leads to combined methylmalonic acidemia and homocysteinemia. The disease is characterized by the presence of methylmalonic acidemia and hyperhomocysteinemia, leading to widespread clinical manifestations affecting multiple organs. … Rationale: MMACHC deficiency leads to combined methylmalonic acidemia and homocysteinemia. The disease is characterized by the presence of methylmalonic acidemia and hyperhomocysteinemia, leading to widespread clinical manifestations affecting multiple organs. Due to the low incidence of cblC deficiency and the diversity of its clinical phenotypes, diagnosis was challenging and often results in delays or missed diagnoses. We now report a case of a male patient who experienced fluctuating cognitive impairment and headaches for 3 times. He was initially diagnosed with encephalitis and venous sinus thrombosis, but his symptoms recurred. Later, significantly elevated levels of homocysteine and methylmalonic acid were detected. Genetic analysis confirmed the presence of a heterozygous mutation in the MMACHC gene, establishing the definitive diagnosis. This case is reported due to its rarity and diverse clinical presentations, highlighting the need for increased awareness of this condition. Patient concerns: A male patient exhibited recurrent episodes of fluctuating cognitive impairment and headaches. Diagnoses: The patient underwent magnetic resonance imaging, lumbar puncture, and cerebrospinal fluid analysis. To confirm the diagnosis, genetic sequencing analysis was also conducted. Interventions: In terms of intervention, the patient received supplementation with cobamamide, vitamin B1, and folic acid, leading to gradual relief and improvement of symptoms. Outcomes: The patient’s headaches and cognitive impairment symptoms have alleviated, and there have been no recurrences during follow-up. Lessons: To our knowledge, there are few clinical cases of methylmalonic acidemia presenting primarily with episodic cognitive impairment and venous sinus thrombosis. Therefore, it is essential to enhance the recognition and differential diagnosis of such symptoms to improve the accuracy and speed of the disease diagnosis.

The origin of abnormal organic acids in HMG-CoA synthase deficiency

2025-06-01

François‐Guillaume Debray , Emile Van Schaftingen | Molecular Genetics and Metabolism