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Donald M Mock - One of the best experts on this subject based on the ideXlab platform.
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Adequate Intake of Biotin in Pregnancy: Why Bother?
The Journal of nutrition, 2014Co-Authors: Donald M MockAbstract:See corresponding article on page 1977 Frank, symptomatic biotin deficiency is a rare occurrence. The only well-documented cases have occurred in association with total or near total intravenous feeding without biotin supplementation, during chronic consumption of un-denatured egg white, and with inborn errors of metabolism that lead to biotin wasting (1, 2). A single case that does not fit any of these established associations is that of an infant fed a rice-based formula that was presumably very low in biotin (1). However, there are observations suggesting that the absence of overt biotin deficiency does not imply optimal biotin nutritional status. Pregnancy is a clinical condition of particular concern. Studies in several animal species, including mice, hamsters, chickens, and turkeys, showed that biotin deficiency is teratogenic (3). For example, fetuses of marginally biotin-deficient mouse dams have a high incidence of skeletal malformations including >50% incidences of cleft palate, micrognathia, microglossia, and fore- and hind-limb shortening (4). Yet, these mouse dams show only metabolic abnormalities. The dams gain weight normally and show no physical signs of biotin deficiency (3, 4); neither reproductive efficiency nor fetal weight gain is affected. Several observations suggest that this mouse model of biotin deficiency is relevant to human gestation. In these biotin-deficient mouse dams, a 2- to 3-fold increase in urinary excretion of 3-hydroxyisovaleric acid (3HIA)3, which reflects reduced activity of the biotin-dependent enzyme methylcrotonyl–CoA carboxylase, occurs early in the pregnancy; the timing and magnitude of the increase is similar to the 3HIA increase that occurs spontaneously during the first trimester of human pregnancy (3). The increase in 3HIA tends to persist throughout pregnancy and will normalize (or at least return to near normal) with 2 wk of supplementation with 300 μg/d of biotin (5), which is 10 times the current Adequate Intake (AI) for biotin. The women who develop this marginal degree of biotin deficiency gain weight normally during pregnancy and show no overt signs of biotin deficiency (3). The apparent disconnect between a modest reduction in murine maternal biotin status and the major effects on fetal skeletal development might result from the mouse fetus being a notably poor parasite for biotin (3). Indeed, marginal biotin deficiency in the mouse dam results in severe biotin deficiency in the fetus. For example, in dams fed a 5% egg-white diet, hepatic propionyl-CoA carboxylase activity decreases to 70% of that in control dams; however, in the fetuses of these same biotin-deficient dams, hepatic propionyl-CoA carboxylase activity decreases to 14% of the activity of fetuses of the control dams (4, 6). Consistent with this observation, placental transport of biotin is likely inadequate both in human pregnancy and in mice (1, 3). In this context, the article by Perry et al. (7) reported in this issue of The Journal of Nutrition is a landmark study. This is the first human pregnancy study that controlled dietary biotin intake and is also the first to quantitate the biotin content of the diet. This is the first ever study that controlled and quantitated biotin intake in lactating women and in the comparison nonpregnant women. Solid evidence of increased 3HIA excretion is provided, confirming previous reports that marginal biotin deficiency occurs spontaneously in a substantial proportion of women during normal human pregnancy. Moreover, reasonable evidence is provided to support the inference that a biotin intake at least 2–3 times the AI is likely needed to meet the requirement of pregnancy. Whether caused by genetic defects or by biotin deficiency (1, 2), reduced activity of Methylcrotonyl-CoA carboxylase leads to accumulation of its substrate 3-methylcrotonyl CoA. Because acyl-CoA compounds are compartmentalized within the mitochondria, accumulation of 3-methylcrotonyl CoA and 3-hydroxyisovaleryl CoA would lead to a disruption of the esterified CoA to free CoA ratios and, ultimately, to potentially lethal mitochondrial toxicity (8, 9). To prevent this, 3HIA-CoA is detoxified by carnitine transesterification to 3HIA-carnitine (3HIAc). The reaction is catalyzed by carnitine acetyltransferase, which is one of a family of enzymes with varying chain length specificity and organelle and organ distribution; these act in concert with transfer of the acylcarnitine out of the mitochondria by carnitine-acylcarnitine translocase to defend the CoA ratios (9). Accumulating 3HIAc is transferred across the inner mitochondrial membrane by the translocase, leading to increased plasma and urinary 3HIAc and 3HIA (10, 11) and potentially to secondary carnitine deficiency (12). 3HIA likely arises preferentially from hydrolysis of 3HIAc in the cytosol. Urinary 3HIAc is a sensitive indicator of marginal biotin deficiency in healthy adults in whom biotin deficiency is induced experimentally (10). Interestingly, urinary excretion of 3HIAc was actually lower among pregnant women than in nonpregnant control women, indicating that urinary 3HIAc is not a reliable indicator of marginal biotin deficiency in pregnancy. We have observed this same unreliability of urinary 3HIAc in pregnancy (unpublished data). Our research group confirmed the metabolic pathogenesis presented above in hepatocyte culture by inducing separate and combined biotin and carnitine deficiency (13). Thus, the assertion by Perry et al. that failure of urinary 3HIAc to increase in parallel with urinary 3HIA is evidence of functional hepatic carnitine deficiency is reasonable and consistent with established biochemical mechanisms. This observation raises the possibility that this functional carnitine deficiency impairs an important cellular detoxification mechanism that defends mitochondrial energetics. The article by Perry et al. also offers intriguing observations concerning biotin metabolism. Accelerated biotransformation of biotin to bisnorbiotin, an inactive metabolite created by β oxidation of the valeric acid side chain, has been observed in early pregnancy, but bisnorbiotin excretion had returned to normal by late in pregnancy (14), consistent with the observations of Perry et al. who observed normal metabolite excretion as well as normal plasma concentrations of biotin and biotin metabolites. Thus, the pathogenesis of biotin deficiency in pregnancy remains to be elucidated. Of note, Perry et al. did observe substantially increased excretion of bisnorbiotin during lactation, which was accompanied by decreased, rather than increased, 3HIA excretion. Finally, the work of Perry et al. (7) is commendable from an additional standpoint. In a time in which competition for extramural and intramural funding to support biomedical research in an academic environment is particularly difficult, these investigators demonstrated admirable foresight in conducting the original randomized choline intervention study in a way that permitted further research. Moreover, these investigators exhibit admirable creativity in considering an additional micronutrient, admirable resourcefulness in adapting the sample availability to study biotin nutrition, and appropriate candor in describing the adaptation. In summary, the article by Perry et al. makes fundamental observations about biotin status in pregnancy and lactation, offers reasonable inferences concerning inadequacy of the current AI for biotin in pregnancy, and raises intriguing questions about the resulting metabolic disturbances and interactions of those disturbances with carnitine status that might impair a mitochondrial defense mechanism. Hamid Said, an eminent investigator in biotin nutrition and physiology, asked more than a decade ago (15): “Biotin bioavailability and adequate intake: why bother?” The study by Perry et al. provides new evidence that the bother is worthwhile.
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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 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 beta-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.
William L. Nyhan - One of the best experts on this subject based on the ideXlab platform.
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Mutant Holocarboxylase Synthetase EVIDENCE FOR THE ENZYME DEFECT IN EARLY INFANTILE BIOTIN- RESPONSIVE MULTIPLE CARBOXYLASE DEFICIENCY
2016Co-Authors: Betty J. Burm, L Sweetman, William L. NyhanAbstract:ase deficiency is an inherited disorder of organic acid metabolism in man in which there are deficiencies of propionyl-coenzyme A (CoA), 3-Methylcrotonyl-CoA, and pyruvate carboxylases that can be corrected with large doses of biotin. It has been proposed that the basic defect in patients with the early infantile form of the disease is in holocarboxylase synthetase, the enzyme that covalently attaches biotin to the inactive apocarboxylases to form active holocarboxylases. We have developed an assay for holocarboxylase synthe-tase in extracts of human fibroblasts using as substrate apopropionyl-CoA carboxylase partially purified from livers of biotin-deficient rats. Fibroblasts from the initial patient with the infantile form of biotin-respon-sive multiple carboxylase deficiency were shown to have abnormal holocarboxylase synthetase activity with a maximum velocity about 30-40 % of normal, a Km for ATP of 0.3 mM similar to the normal Km of 0.2 mM, and a highly elevated Km for biotin of 126 ng/ml, about 60 times the normal Km of 2 ng/ml. These results show that the primary defect in this patient is a mutation affecting holocarboxylase synthetase activity, and thus a genetic defect of the metabolism of biotin
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Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria
Molecular Genetics and Metabolism, 2011Co-Authors: Khue Vu Nguyen, Bruce A. Barshop, Satyajit Patra, Robert K. Naviaux, William L. NyhanAbstract:Methylcrotonylglycinuria (MCG) is an inborn error of leucine catabolism and has a recessive pattern of inheritance that results from the deficiency of 3-Methylcrotonyl-CoA carboxylase (MCC). The clinical phenotypes are highly variable ranging from neonatal onset with severe neurological involvement to asymptomatic adults. Here we identified two novel MCCA (exon 3: c.137G>A; p.46G>E), (IVS7-1G>A splice site mutation), and four novel MCCB (exon 11: c.1065A>T; p.355L>F), (exon 15: c.1430A>G; p.477Q>R), (exon 16: c.1549G>A; p.517G>R), (exon 16: c.1559A>C; p.520Y>S) mutant alleles from five MCC-deficient patients. © 2010.
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prenatal diagnosis and treatment of holocarboxylase synthetase deficiency
Prenatal Diagnosis, 1999Co-Authors: L P Thuy, John W Belmont, William L. NyhanAbstract:Holocarboxylase synthetase is one of two enzymes known to be involved in the metabolism of biotin. It catalyses the fixation of biotin to inactive apocarboxylases yielding active carboxylases. Deficiency of this enzyme leads to multiple carboxylase deficiency which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase prenatal diagnosis was performed by assay of the enzyme in amniocytes. The Km for biotin was 62·8nM which was 12 times the control value of 5·0nM. The Vmax was 2 per cent of the control value. This was confirmed by assay of the activity of propionyl CoA carboxylase (20–26 per cent control), 3-methylcrotonyl CoA carboxylase (14–19 per cent control) and pyruvate carboxylase (12–30 per cent control) and demonstration of biotin responsiveness in vitro. All carboxylase activities were restored to 51–58 per cent of control when amnio-cytes were cultured in medium containing 1μM biotin. Diagnosis was ultimately confirmed by assay of holocarboxylase synthetase in lymphocytes from the infant after birth. The Km for biotin of the holocarboxylase synthetase of the infant was 60·3nM while that of a parallel control was 6·9nM. Prenatal treatment of the mother with biotin led to a concentration of biotin of 240nM in the serum of the infant at birth that was four times the Km of the enzyme for biotin. The infant was clinically well at birth, and organic acid analysis of the blood and urine revealed no accumulation of the characteristic metabolites. Copyright © 1999 John Wiley & Sons, Ltd.
Liang Tong - One of the best experts on this subject based on the ideXlab platform.
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Structure and function of biotin-dependent carboxylases
Cellular and Molecular Life Sciences, 2013Co-Authors: Liang TongAbstract:Biotin-dependent carboxylases include acetyl-CoA carboxylase (ACC), propionyl-CoA carboxylase (PCC), 3-Methylcrotonyl-CoA carboxylase (MCC), geranyl-CoA carboxylase, pyruvate carboxylase (PC), and urea carboxylase (UC). They contain biotin carboxylase (BC), carboxyltransferase (CT), and biotin-carboxyl carrier protein components. These enzymes are widely distributed in nature and have important functions in fatty acid metabolism, amino acid metabolism, carbohydrate metabolism, polyketide biosynthesis, urea utilization, and other cellular processes. ACCs are also attractive targets for drug discovery against type 2 diabetes, obesity, cancer, microbial infections, and other diseases, and the plastid ACC of grasses is the target of action of three classes of commercial herbicides. Deficiencies in the activities of PCC, MCC, or PC are linked to serious diseases in humans. Our understanding of these enzymes has been greatly enhanced over the past few years by the crystal structures of the holoenzymes of PCC, MCC, PC, and UC. The structures reveal unanticipated features in the architectures of the holoenzymes, including the presence of previously unrecognized domains, and provide a molecular basis for understanding their catalytic mechanism as well as the large collection of disease-causing mutations in PCC, MCC, and PC. This review will summarize the recent advances in our knowledge on the structure and function of these important metabolic enzymes.
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an unanticipated architecture of the 750 kda α6β6 holoenzyme of 3 methylcrotonyl coa carboxylase
Nature, 2012Co-Authors: Christine S Huang, Hong Z Zhou, Liang TongAbstract:3-Methylcrotonyl-CoA carboxylase (MCC), a member of the biotin-dependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglycinuria (MCG) and other serious diseases in humans. MCC has strong sequence conservation with propionyl-CoA carboxylase (PCC), and their holoenzymes are both 750-kilodalton (kDa) α(6)β(6) dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are markedly different when compared to PCC. The α-subunits show trimeric association in the PaMCC holoenzyme, whereas they have no contacts with each other in PCC. Moreover, the positions of the two domains in the β-subunit of PaMCC are swapped relative to those in PCC. This structural information establishes a foundation for understanding the disease-causing mutations of MCC and provides new insights into the catalytic mechanism and evolution of biotin-dependent carboxylases. The large structural differences between MCC and PCC also have general implications for the relationship between sequence conservation and structural similarity.
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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biotin deficiency reduces expression of slc19a3 a potential biotin transporter in leukocytes from human blood
Experimental biology, 2005Co-Authors: Tatyana I Vlasova, Nell I Mock, Shawna L Stratton, Amanda M Wells, Donald M MocksAbstract:In evaluating potential indicators of biotin status, we quantitated the expression of biotin-related genes in leukocytes from human blood of normal subjects before and after inducing marginal biotin deficiency. Biotin deficiency was induced experimentally by feeding an egg-white diet for 28 d. Gene expression was quantitated for the following biotin-related proteins: Methylcrotonyl-CoA carboxylase chains A (MCCA) and B (MCCB); propionyl-CoA carboxylase chains A (PCCA) and B (PCCB); pyruvate carboxylase (PC); acetyl-CoA carboxylase isoforms A (ACCA) and B (ACCB); holocarboxylase synthetase (HCS); biotinidase; and 2 potential biotin transporters: sodium-dependent multivitamin transporter (SMVT) and solute carrier family 19 member 3 (SLC19A3). For 7 subjects who successfully completed the study, the abundance of the specific mRNAs was determined by quantitative real-time RT-PCR at d 0 and 28. At d 28, SLC1 9A3 expression had decreased to 33% of d 0 (P < 0.02 by two-tailed, paired t test). Expression of MCCA, PCCA, PC, ACCA, ACCB, HCS, biotinidase, and SMVT decreased to ∼80% of d 0 (P < 0.05). Expression of the MCCB and PCCB chains that do not carry the biotin-binding motif did not change significantly; we speculate that expression of the biotin-binding chains of biotin-dependent carboxylases is more responsive to biotin status changes. These data provide evidence that expression of SLC19A3 is a relatively sensitive indicator of marginal 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.
Terttu Suormala - One of the best experts on this subject based on the ideXlab platform.
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3 methylcrotonyl coa carboxylase deficiency clinical biochemical enzymatic and molecular studies in 88 individuals
Orphanet Journal of Rare Diseases, 2012Co-Authors: Sarah C Grunert, Terttu Suormala, Martin Stucki, Raphael J Morscher, Celine Burer, Patricie Burda, E Christensen, Can Ficicioglu, Jurgen HerwigAbstract:Isolated 3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults. We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby. Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date. Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course.
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3 methylcrotonyl coa carboxylase deficiency mutation analysis in 28 probands 9 symptomatic and 19 detected by newborn screening
Human Mutation, 2005Co-Authors: Maria Fernanda Dantas, Terttu Suormala, Brian Fowler, David Valle, Ann Randolph, David Coelho, Matthias R BaumgartnerAbstract:Isolated 3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder that appears to be the most frequent organic aciduria detected in tandem mass spectrometry (TMS)-based neonatal screening programs. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. MCC is a heteromeric mitochondrial enzyme composed of biotin containing alpha subunits and smaller beta subunits, encoded by MCCA and MCCB, respectively. We report mutation analysis in 28 MCC-deficient probands, 19 of whom were asymptomatic newborns detected by TMS newborn screening, and nine presented with clinical symptoms. Ten have mutations in MCCA, and 18 in MCCB. We identified 10 novel MCCA and 14 novel MCCB mutant alleles including missense, nonsense, frameshift and splice site mutations, and show that three of the missense mutations result in severely decreased MCC activity when expressed in MCC-deficient cell lines. Our data demonstrate no clear correlation between genotype and phenotype suggesting that factors other than the genotype at the MCC loci have a major influence on the phenotype of MCC deficiency.
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the molecular basis of human 3 methylcrotonyl coa carboxylase deficiency
Journal of Clinical Investigation, 2001Co-Authors: Matthias R Baumgartner, Terttu Suormala, Shlomo Almashanu, Seymour Packman, Cassandra Obie, Robert N Cole, Regula E Baumgartner, David ValleAbstract:Isolated biotin-resistant 3-Methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine catabolism that appears to be the most frequent organic aciduria detected in tandem mass spectrometry-based neonatal screening programs. The phenotype is variable, ranging from neonatal onset with severe neurological involvement to asymptomatic adults. MCC is a heteromeric mitochondrial enzyme composed of biotin-containing alpha subunits and smaller beta subunits. Here, we report cloning of MCCA and MCCB cDNAs and the organization of their structural genes. We show that a series of 14 MCC-deficient probands defines two complementation groups, CG1 and 2, resulting from mutations in MCCB and MCCA, respectively. We identify five MCCA and nine MCCB mutant alleles and show that missense mutations in each result in loss of function.
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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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holocarboxylase synthetase deficiency early diagnosis and management of a new case
European Journal of Pediatrics, 1993Co-Authors: A Fuchshuber, Terttu Suormala, M Duran, B Roth, D Michalk, E R BaumgartnerAbstract:We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the “early-onset” form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonyglycine, 3-hydroxypropionic acid and methylcritric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10−8 mol/l) but normal in a high biotin medium (10−5 mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%–29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patient's physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.