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Donald M Mock - One of the best experts on this subject based on the ideXlab platform.
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marginal biotin deficiency is common in normal human pregnancy and is highly teratogenic in mice
Journal of Nutrition, 2009Co-Authors: Donald M MockAbstract:In studies of marginal biotin deficiency induced experimentally in adults, increased urinary excretion of 3-hydroxyisovaleric acid (3HIA), which likely reflects decreased activity of the biotin-dependent enzyme β-Methylcrotonyl-CoA Carboxylase, and decreased activity of the biotin-dependent enzyme propionyl-CoA Carboxylase (PCC) in peripheral blood lymphocytes have been validated as indices of biotin status. About half of pregnant women excrete increased amounts of urinary 3HIA. However, interpretation of urinary 3HIA excretion rates is problematic, because renal function is altered by pregnancy per se. In a recent pilot study, activity of PCC in peripheral blood lymphocytes was decreased in 18 of 22 pregnant women. In 4 of 4 pregnant women with decreased PCC activity, biotin supplementation caused increased PCC activity by a mean of 95%. Taken together, such studies provide evidence that a substantial proportion of pregnant women are marginally biotin deficient. In mice, degrees of biotin deficiency that are metabolically similar to those seen in pregnant women are very teratogenic. Moreover, in mice, a marginal degree of biotin deficiency in the dam causes a much more severe degree of deficiency in the fetus. These observations further raise concerns that biotin deficiency does occur and does cause human birth defects.
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marginal biotin deficiency is teratogenic in mice and perhaps humans a review of biotin deficiency during human pregnancy and effects of biotin deficiency on gene expression and enzyme activities in mouse dam and fetus
Journal of Nutritional Biochemistry, 2005Co-Authors: Donald M MockAbstract:Recent studies of biotin status during pregnancy provide evidence that a marginal degree of biotin deficiency develops in a substantial proportion of women during normal pregnancy. Several lines of evidence suggest that although the degree of biotin deficiency is not severe enough to produce the classic cutaneous and behavioral manifestations of biotin deficiency, the deficiency is severe enough to produce metabolic derangements in women and may be teratogenic. In studies of mice, a similar degree of biotin deficiency induces characteristic fetal malformations at a high rate. Fetal hepatic biotin content and PCC activity decrease indicating that the fetuses also become biotin deficient. Fetal hepatic acetyl-CoA Carboxylase, pyruvate Carboxylase, propionyl-CoA Carboxylase and β-Methylcrotonyl-CoA Carboxylase abundances determined by Western blotting decreased more than the dam holoCarboxylase abundances (10% of sufficient vs. 50% of sufficient); however, hepatic mRNA for the Carboxylases and for HCS did not change significantly in either dams or fetuses. These observations suggest that maternal biotin deficiency results in a lack of adequate biotin to biotinylate apoCarboxylases in the fetus despite the normal expression of genes coding for the apoCarboxylases and holoCarboxylase synthetase.
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biotin deficiency reduces expression of slc19a3 a potential biotin transporter in leukocytes from human blood
Journal of Nutrition, 2005Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M MockAbstract:Biotin deficiency is teratogenic in mice (1,2) and may be teratogenic in humans (3). Valid indicators of marginal and moderate biotin deficiency would be useful in investigating the role of biotin deficiency in birth defects and in other illnesses hypothesized to be biotin related (4 –7). Emerging evidence indicates that biotin plays a role in gene expression (8 –12). In addition to acting as a cofactor for biotin-dependent Carboxylases, biotin stimulates expression of hepatic glucokinase (8) and represses expression of hepatic phosphoenolpyruvate Carboxylase (9) in vivo, and expression of the biotin-related enzymes propionyl-CoA Carboxylase chain A (PCCA),4 acetyl-CoA Carboxylase isoform A (ACCA), and holoCarboxylase synthetase (HCS) in cultured human hepatoblastoma cells and normal fibroblasts (10). However, no such studies have been performed in humans in vivo. In this study, we examined the expression of specific biotin-related genes as indicators of marginal, asymptomatic biotin deficiency and assessed gene response to marginal biotin deficiency. In mammals, biotin is a coenzyme for 5 biotin-dependent Carboxylases: Methylcrotonyl-CoA Carboxylase (MCC), propionyl-CoA Carboxylase (PCC), pyruvate Carboxylase (PC), and the 2 isoforms of ACC (ACCA and ACCB). The active forms of the enzymes (holoCarboxylases) contain biotin covalently bound to lysine residues; the attachment of biotin to the corresponding apoCarboxylase is catalyzed by HCS. Biotin is transported into eukaryotic cells by biotin transporters located in cell membranes. Three biotin transporters have been proposed in human cells: 1) the sodium-dependent multivitamin transporter (SMVT) (13,14); 2) the solute carrier family 19 member 3 (SLC19A3) (15,16); and 3) the monocarboxylate transporter R1 (17). This third transporter was proposed after this study was initiated and was not examined here. Biotinidase catalyzes the release of covalently bound biotin from biotinyl-peptides generated by the turnover of intracellular proteins and releases biotin from dietary proteins during digestion (18). Biotinidase is also likely important in catalyzing the covalent binding of biotin to histones (19). In this study, we evaluated expression of biotin-related genes as potential indicators of marginal, asymptomatic biotin deficiency. Gene expression was quantitated in leukocytes of 7 healthy humans after 28 d of progressive biotin deficiency.
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marginal maternal biotin deficiency in cd 1 mice reduces fetal mass of biotin dependent Carboxylases
Experimental Biology '04. Symposium, 2005Co-Authors: Wendy M Sealey, Shawna L Stratton, Donald M Mock, Deborah K HansenAbstract:Marginal maternal biotin deficiency reduces hepatic activity of biotin-dependent Carboxylases and causes high rates of fetal birth defects in mice. We tested the hypothesis that the decreased Carboxylase activity observed in deficient dams and their offspring is mediated by decreased abundance of biotinylated Carboxylases, decreased expression of their mRNAs, or both. During gestation, CD-1 mice were fed a diet that induced biotin deficiency or a biotin-sufficient diet. On gestational d 17, gravid uteri were removed, and each live fetus was examined grossly for defects. The expected high incidence of cleft palate (83%) in offspring was observed. In maternal and fetal liver, acetyl-CoA Carboxylase, pyruvate Carboxylase, propionyl-CoA Carboxylase, and β-Methylcrotonyl-CoA Carboxylase abundances were determined by Western blotting; the content of mRNAs for most of these enzymes and holoCarboxylase synthetase was determined by real-time RT-PCR. Biotin deficiency significantly reduced the abundance of the Carboxylases in maternal and fetal liver; neither the content of mRNAs for the Carboxylases nor holoCarboxylase synthetase changed. This study provides evidence that the decrease in Carboxylase activities is attributable to a decrease in the abundance of biotinylated Carboxylases; further, this effect is more severe in fetuses than dams.
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3 hydroxypropionic acid and methylcitric acid are not reliable indicators of marginal biotin deficiency in humans
Journal of Nutrition, 2004Co-Authors: Donald M Mock, Cindy L Henrichshell, Nadine Carnell, Phyllis J Stumbo, Nell I MockAbstract:In two studies comprising 10 and 11 subjects, respectively, marginal biotin deficiency was induced experimentally by an egg-white diet in healthy men and women. The following urinary organic acids were assessed for their usefulness in detecting marginal biotin status: 1) 3-hydroxypropionic acid and methylcitric acid, organic acids that reflect decreased activity of the biotin-dependent enzyme propionyl-CoA Carboxylase and 2) methylcrotonylglycine and isovalerylglycine, organic acids that reflect decreased activity of Methylcrotonyl-CoA Carboxylase. Mean 3-hydroxypropionic acid excretion rates remained normal during biotin depletion in both studies. By the end of the depletion period, 3-hydroxypropionic acid excretion identified only 5 of 21 marginally deficient subjects. Mean methylcitric acid excretion increased (P < 0.0001) in the first study but not in the second. Mean methylcrotonylglycine excretion increased in each study (P < 0.004 and P < 0.05, respectively); methylcrotonylglycine excretion identified 13 of 21 marginally deficient subjects. Mean isovalerylglycine excretion increased only in the first study (P = 0.006) and identified only 6 of 21 deficient subjects. We conclude that none of these organic acids is as sensitive an indicator of marginal biotin deficiency as 3-hydroxyisovaleric acid, which reflects decreased Methylcrotonyl-CoA Carboxylase.
Terttu Suormala - One of the best experts on this subject based on the ideXlab platform.
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Leukodystrophy and CSF purine abnormalities associated with isolated 3-Methylcrotonyl-CoA Carboxylase deficiency
Metabolic Brain Disease, 2002Co-Authors: Raquel Dodelson De Kremer, Alexandra Latini, Laura Larovere, Ana Paschini-capra, Catalina Depetris-boldinil, Norberto Guelbert, Terttu Suormala, E. Regula Baumgartner, Gabriel Civallero, Carlos Quiroga MayorAbstract:We report the first case of isolated biotin resistant 3-Methylcrotonyl-CoA Carboxylase (MCC) deficiency in Argentina. The diagnosis was established at 14 months of age by urinary organic-acid analysis and confirmed by enzyme assay in fibroblasts. The patient suffered from severe psychomotor retardation, hypotonia, areflexia, and failure to thrive, and died unexpectedly at 3 years 4 months of life. Brain MRI at 14 months showed signals of the white matter on cerebral T2-weighted, which were indicative of confluent and multiple foci of leukodystrophy, a pattern not previously described in this entity. In addition, high levels of oxypurines were detected in cerebrospinal fluid. This might be related to energetic consequences of the enzyme deficiency in the brain. This case extends the phenotype of isolated MCC deficiency in infancy and suggests this entity should be considered to be one of the possible causes of "metabolic leukodystrophies.".
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isolated biotin resistant 3 methylcrotonyl coa Carboxylase deficiency long term outcome in a case with neonatal onset
European Journal of Pediatrics, 1996Co-Authors: W Lehnert, Terttu Suormala, H Niederhoff, E R BaumgartnerAbstract:A patient with early-onset 3-methylcrotonyl coenzyme A Carboxylase (MCC) deficiency showing a severe clinical course is described. Abnormal eye and head movements suggestive of seizures were noticed soon after birth. Tonic convulsions at the age of 10 weeks led to admission. Urinary organic acid analysis using gas chromatography-mass spectrometry at 3 months of age revealed elevated concentrations of 3-hydroxyisovaleric acid (3HIVA) and 3-methylcrotonylglycine but normal levels of lactate, 3-hydroxypropionate and methylcitrate suggesting isolated MCC deficiency. This was confirmed by enzyme assays in lymphocytes and cultured skin fibroblasts: MCC activity was virtually undetectable whereas activities of propionyl-CoA and pyruvate Carboxylases were within the normal range. A low protein (0.8–1.5 g/kg/day) diet supplemented with a leucine-free amino acid mixture resulted in a marked decrease of 3HIVA excretion.l-Carnitine and biotin administration had no effect on the clinical condition or metabolite exretion. Supplementation with glycine resulted in only a temporary fall of 3HIVA excretion and was therefore discontinued.l-Carnitine therapy was reintroduced later because of secondary carnitine deficiency. Compliance with treatment was poor until the age of 27 months resulting in a severe episode with seizures and coma. The general clinical condition of the patient was always good but his psychomotor development was delayed and seizures were not continuously under good control due to poor therapy compliance. The boy is now 10.5 years old and attending a school for children with learning handicaps.
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Isolated biotin-resistant deficiency of 3-Methylcrotonyl-CoA Carboxylase presenting as a clinically severe form in a newborn with fatal outcome
Journal of Inherited Metabolic Disease, 1992Co-Authors: Cyrill Bannwart, Terttu Suormala, Bendicht Wermuth, Richard Baumgartner, Ulrich N. WiesmannAbstract:The son of Kurdish, consanguineous parents (cousin marriage) presented from the first day of life with initially focal and later generalized attacks of epileptic seizures and a severe generalized muscular hypotonia. Urinary excretion of 3-hydroxyisovalerate and of 3-methylcrotonylglycine was persistently increased. Diagnosis of isolated biotin-resistant 3-Methylcrotonyl-CoA Carboxylase deficiency was confirmed in cultured fibroblasts. Psychomotor retardation was progressive, seizures and marked EEG abnormalities persisted. Treatment with leucine and protein-resistricted diet under hospital control did not significantly improve these conditions. The patient died from a cardiac and circulatory failure after a prolonged epileptic attack, with bronchial aspiration. The non-responsiveness of our patient to therapy and the fatal outcome indicate the existence of a severe neonatal variant of this otherwise rather benign genetic enzyme deficiency.
George F Grady - One of the best experts on this subject based on the ideXlab platform.
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tandem mass spectrometric analysis for amino organic and fatty acid disorders in newborn dried blood spots a two year summary from the new england newborn screening program
Clinical Chemistry, 2001Co-Authors: Thomas H Zytkovicz, Eileen F Fitzgerald, Deborah Marsden, Cecilia Larson, Vivian E Shih, Donna M Johnson, Arnold W Strauss, Anne Marie Comeau, Roger B Eaton, George F GradyAbstract:BACKGROUND: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. METHODS: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in approximately 1.9 min. Cutoffs for each marker were set at 6-13 SD above the population mean. RESULTS: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 Methylcrotonyl-CoA Carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. CONCLUSIONS: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.
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tandem mass spectrometric analysis for amino organic and fatty acid disorders in newborn dried blood spots a two year summary from the new england newborn screening program
Clinical Chemistry, 2001Co-Authors: Thomas H Zytkovicz, Eileen F Fitzgerald, Vivian E Shih, Arnold W Strauss, Anne Marie Comeau, Deborah Marsde, Cecilia Larso, Donna M Johnso, Roge Eato, George F GradyAbstract:Background: Tandem mass spectrometry (MS/MS) is rapidly being adopted by newborn screening programs to screen dried blood spots for >20 markers of disease in a single assay. Limited information is available for setting the marker cutoffs and for the resulting positive predictive values. Methods: We screened >160 000 newborns by MS/MS. The markers were extracted from blood spots into a methanol solution with deuterium-labeled internal standards and then were derivatized before analysis by MS/MS. Multiple reaction monitoring of each sample for the markers of interest was accomplished in ∼1.9 min. Cutoffs for each marker were set at 6–13 SD above the population mean. Results: We identified 22 babies with amino acid disorders (7 phenylketonuria, 11 hyperphenylalaninemia, 1 maple syrup urine disease, 1 hypermethioninemia, 1 arginosuccinate lyase deficiency, and 1 argininemia) and 20 infants with fatty and organic acid disorders (10 medium-chain acyl-CoA dehydrogenase deficiencies, 5 presumptive short-chain acyl-CoA dehydrogenase deficiencies, 2 propionic acidemias, 1 carnitine palmitoyltransferase II deficiency, 1 Methylcrotonyl-CoA Carboxylase deficiency, and 1 presumptive very-long chain acyl-CoA dehydrogenase deficiency). Approximately 0.3% of all newborns screened were flagged for either amino acid or acylcarnitine markers; approximately one-half of all the flagged infants were from the 5% of newborns who required neonatal intensive care or had birth weights <1500 g. Conclusions: In screening for 23 metabolic disorders by MS/MS, an mean positive predictive value of 8% can be achieved when using cutoffs for individual markers determined empirically on newborns.
E R Baumgartner - One of the best experts on this subject based on the ideXlab platform.
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the first case of 3 methylcrotonyl coa Carboxylase mcc deficiency responsive to biotin
Neuropediatrics, 2006Co-Authors: D Friebel, Matthias R. Baumgartner, M Von Der Hagen, E R Baumgartner, Brian Fowler, G Hahn, P Feyh, Georg Heubner, Georg F HoffmannAbstract:: 3-Methylcrotonylglycinuria is an inborn error of leucine catabolism with an autosomal recessive pattern of inheritance that results from a deficiency of 3-Methylcrotonyl-CoA Carboxylase (MCC). We report on a nine-year-old boy with severe psychomotor retardation who developed infantile spasms at the age of three weeks. Urine analysis at the age of two years revealed massive 3-methylcrotonylglycinuria and 3-hydroxyisovaleric aciduria suggesting MCC deficiency. Carnitine serum levels were decreased. Biotin therapy led to a dramatic decrease in the frequency of seizures, disappearance of hypsarrhythmia, and near normalisation of organic aciduria. Four months later a protein-restricted diet was introduced in addition and the boy remained clinically and metabolically stable. However, severe psychomotor delay persisted, and the seizures partially reoccurred. Biochemical findings showed partial MCC deficiency in cultured fibroblasts. Molecular genetic studies revealed a heterozygote missense mutation, MCCA-R385S, converting arginine to serine in a highly conserved region of the MCCA gene. This is the first patient with MCC deficiency caused by a heterozygote mutation and who demonstrated a substantial and sustained clinical and biochemical response to therapeutic doses of biotin. Sadly, this patient again also demonstrates that the main determinant of the outcome of even easily treatable metabolic diseases is timely diagnosis.
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isolated biotin resistant 3 methylcrotonyl coa Carboxylase deficiency long term outcome in a case with neonatal onset
European Journal of Pediatrics, 1996Co-Authors: W Lehnert, Terttu Suormala, H Niederhoff, E R BaumgartnerAbstract:A patient with early-onset 3-methylcrotonyl coenzyme A Carboxylase (MCC) deficiency showing a severe clinical course is described. Abnormal eye and head movements suggestive of seizures were noticed soon after birth. Tonic convulsions at the age of 10 weeks led to admission. Urinary organic acid analysis using gas chromatography-mass spectrometry at 3 months of age revealed elevated concentrations of 3-hydroxyisovaleric acid (3HIVA) and 3-methylcrotonylglycine but normal levels of lactate, 3-hydroxypropionate and methylcitrate suggesting isolated MCC deficiency. This was confirmed by enzyme assays in lymphocytes and cultured skin fibroblasts: MCC activity was virtually undetectable whereas activities of propionyl-CoA and pyruvate Carboxylases were within the normal range. A low protein (0.8–1.5 g/kg/day) diet supplemented with a leucine-free amino acid mixture resulted in a marked decrease of 3HIVA excretion.l-Carnitine and biotin administration had no effect on the clinical condition or metabolite exretion. Supplementation with glycine resulted in only a temporary fall of 3HIVA excretion and was therefore discontinued.l-Carnitine therapy was reintroduced later because of secondary carnitine deficiency. Compliance with treatment was poor until the age of 27 months resulting in a severe episode with seizures and coma. The general clinical condition of the patient was always good but his psychomotor development was delayed and seizures were not continuously under good control due to poor therapy compliance. The boy is now 10.5 years old and attending a school for children with learning handicaps.
Nell I Mock - One of the best experts on this subject based on the ideXlab platform.
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biotin deficiency reduces expression of slc19a3 a potential biotin transporter in leukocytes from human blood
Journal of Nutrition, 2005Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M MockAbstract:Biotin deficiency is teratogenic in mice (1,2) and may be teratogenic in humans (3). Valid indicators of marginal and moderate biotin deficiency would be useful in investigating the role of biotin deficiency in birth defects and in other illnesses hypothesized to be biotin related (4 –7). Emerging evidence indicates that biotin plays a role in gene expression (8 –12). In addition to acting as a cofactor for biotin-dependent Carboxylases, biotin stimulates expression of hepatic glucokinase (8) and represses expression of hepatic phosphoenolpyruvate Carboxylase (9) in vivo, and expression of the biotin-related enzymes propionyl-CoA Carboxylase chain A (PCCA),4 acetyl-CoA Carboxylase isoform A (ACCA), and holoCarboxylase synthetase (HCS) in cultured human hepatoblastoma cells and normal fibroblasts (10). However, no such studies have been performed in humans in vivo. In this study, we examined the expression of specific biotin-related genes as indicators of marginal, asymptomatic biotin deficiency and assessed gene response to marginal biotin deficiency. In mammals, biotin is a coenzyme for 5 biotin-dependent Carboxylases: Methylcrotonyl-CoA Carboxylase (MCC), propionyl-CoA Carboxylase (PCC), pyruvate Carboxylase (PC), and the 2 isoforms of ACC (ACCA and ACCB). The active forms of the enzymes (holoCarboxylases) contain biotin covalently bound to lysine residues; the attachment of biotin to the corresponding apoCarboxylase is catalyzed by HCS. Biotin is transported into eukaryotic cells by biotin transporters located in cell membranes. Three biotin transporters have been proposed in human cells: 1) the sodium-dependent multivitamin transporter (SMVT) (13,14); 2) the solute carrier family 19 member 3 (SLC19A3) (15,16); and 3) the monocarboxylate transporter R1 (17). This third transporter was proposed after this study was initiated and was not examined here. Biotinidase catalyzes the release of covalently bound biotin from biotinyl-peptides generated by the turnover of intracellular proteins and releases biotin from dietary proteins during digestion (18). Biotinidase is also likely important in catalyzing the covalent binding of biotin to histones (19). In this study, we evaluated expression of biotin-related genes as potential indicators of marginal, asymptomatic biotin deficiency. Gene expression was quantitated in leukocytes of 7 healthy humans after 28 d of progressive biotin deficiency.
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3 hydroxypropionic acid and methylcitric acid are not reliable indicators of marginal biotin deficiency in humans
Journal of Nutrition, 2004Co-Authors: Donald M Mock, Cindy L Henrichshell, Nadine Carnell, Phyllis J Stumbo, Nell I MockAbstract:In two studies comprising 10 and 11 subjects, respectively, marginal biotin deficiency was induced experimentally by an egg-white diet in healthy men and women. The following urinary organic acids were assessed for their usefulness in detecting marginal biotin status: 1) 3-hydroxypropionic acid and methylcitric acid, organic acids that reflect decreased activity of the biotin-dependent enzyme propionyl-CoA Carboxylase and 2) methylcrotonylglycine and isovalerylglycine, organic acids that reflect decreased activity of Methylcrotonyl-CoA Carboxylase. Mean 3-hydroxypropionic acid excretion rates remained normal during biotin depletion in both studies. By the end of the depletion period, 3-hydroxypropionic acid excretion identified only 5 of 21 marginally deficient subjects. Mean methylcitric acid excretion increased (P < 0.0001) in the first study but not in the second. Mean methylcrotonylglycine excretion increased in each study (P < 0.004 and P < 0.05, respectively); methylcrotonylglycine excretion identified 13 of 21 marginally deficient subjects. Mean isovalerylglycine excretion increased only in the first study (P = 0.006) and identified only 6 of 21 deficient subjects. We conclude that none of these organic acids is as sensitive an indicator of marginal biotin deficiency as 3-hydroxyisovaleric acid, which reflects decreased Methylcrotonyl-CoA Carboxylase.
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lymphocyte propionyl coa Carboxylase is an early and sensitive indicator of biotin deficiency in rats but urinary excretion of 3 hydroxypropionic acid is not
Journal of Nutrition, 2002Co-Authors: Donald M Mock, Nell I MockAbstract:Recent clinical studies indicate that marginal, asymptomatic biotin deficiency may be a common occurrence in normal human gestation (1–3) and in individuals treated for extended periods with certain anticonvulsants (4 –9). In rats (10) and humans (11), reduced urinary excretion of biotin and increased urinary excretion of 3-hydroxyisovaleric acid (3HIA),3 are early and sensitive indicators of impaired biotin deficiency. Both of these validated indicators depend on renal function. Increased 3HIA excretion reflects decreased activity of the biotin-dependent enzyme Methylcrotonyl-CoA Carboxylase. Development of a valid indicator of biotin status that does not depend on renal function would likely be useful. Unfortunately, the plasma concentration of biotin is not particularly useful in detecting marginal biotin deficiency (11). The concentration of biotin in erythrocytes is similar to the plasma concentration in the same blood sample (unpublished data); thus is not likely to be useful for detecting marginal biotin deficiency. Propionyl-CoA Carboxylase (PCC) is a biotin-dependent enzyme found in a variety of tissues including liver and lymphocytes. Studies of biotin-deficient patients receiving parenteral nutrition (12) or suffering from protein-energy malnutrition (13) suggest that lymphocyte PCC activity reflects biotin status in moderate-to-severe biotin deficiency. Using egg-white–fed rats, a well-established model of biotin deficiency, we sought to determine whether the activity of the PCC in lymphocytes is useful in detecting marginal biotin deficiency. We also evaluated whether urinary excretion of 3-hydroxypropionic acid (3HPA), an organic acid that reflects decreased activity of PCC, is useful in detecting marginal biotin deficiency in this rat model.
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marginal biotin deficiency during normal pregnancy
The American Journal of Clinical Nutrition, 2002Co-Authors: Donald M Mock, Gerald J Quirk, Nell I MockAbstract:Background: Biotin deficiency is teratogenic in several mammalian species. Approximately 50% of pregnant women have an abnormally increased urinary excretion of 3-hydroxyisovaleric acid (3-HIA), which probably reflects decreased activity of the biotindependent enzyme Methylcrotonyl-CoA Carboxylase. However, increased 3-HIA excretion could result from pregnancy per se (eg, from an effect of pregnancy on renal handling of organic acids). Objective: We tested the hypothesis that biotin supplementation significantly decreases 3-HIA excretion in pregnant women with abnormally increased 3-HIA excretion. Design: Twenty-six pregnant women with increased 3-HIA excretion were studied in a randomized, placebo-controlled trial; 10 women were studied during early pregnancy (6‐17 wk gestation) and 16 women during late pregnancy (21‐37 wk gestation). Urine samples were collected before and after 14 d of supplementation with 300 � g (1.2 � mol) biotin/d or placebo. Results: In the early-pregnancy group, 3-HIA excretion decreased (P < 0.006) by 11.7 ± 3.6 mmol/mol creatinine (mean ± SEM) in the 5 women who received biotin supplements, whereas 3-HIA excretion increased by 1.6 ± 0.6 mmol/mol creatinine in the 5 women who received placebo. In the late-pregnancy group, 3-HIA excretion decreased (P < 0.002) by 7.1 ± 1.2 mmol/mol creatinine in the 8 women who received biotin supplements, whereas 3-HIA excretion increased by 0.9 ± 1.8 mmol/mol creatinine in the 8 women who received placebo. Conclusions: This study provides evidence that the increased excretion of 3-HIA seen frequently in normal pregnancy reflects reduced biotin status. The conclusion that marginal biotin deficiency occurs frequently in the first trimester further raises concern about potential human teratogenicity. Am J Clin Nutr 2002;75:295‐9.
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certain immune markers are not good indicators of mild to moderate biotin deficiency in rats
Journal of Nutrition, 2001Co-Authors: Ricki M Helm, Nell I Mock, Pippa Simpson, Donald M MockAbstract:: To assess the effects of marginal biotin deficiency on immune function and thereby evaluate immune function as a potential marker for impaired biotin status, we investigated immune function in a rat model during progression from sufficiency to moderate biotin deficiency. As immune function indicators, we assessed the IgG response to a vaccine and the cytokine responses and relative proportions of lymphocyte subpopulations in the immunocytes in blood, spleen and thymus. Neither phenotype nor organ redistribution of lymphocytes differed between biotin-deficient and biotin-sufficient rats. Assessment of immune function by mitogen T cell proliferation, mitogen-induced interferon-gamma and interleukin-4 levels, IgG antibody responses and natural killer cell activity were not significantly different in mild to moderately biotin-deficient rats compared with biotin-sufficient controls. The absence of effects on immune function was not attributable to failure to induce biotin deficiency; the rats exhibited unequivocal evidence of biotin deficiency, including reduced hepatic biotin and impaired leucine metabolism resulting from deficiency of the biotin-dependent enzyme Methylcrotonyl-CoA Carboxylase. We conclude that the immune markers examined are not promising candidates as indicators of mild to moderate deficiency in humans.