Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria

doi:10.1016/0009-8981(76)90355-7

Clinica Chimica Acta

Volume 70, Issue 3, 2 August 1976, Pages 417-425

https://doi.org/10.1016/0009-8981(76)90355-7 Get rights and content

Abstract

Suberylglycine (HOOC(CH₂)₆CONHCH₂COOH) was found in the urine from a patient with C₆-C₁₀-ω-dicarboxylic aciduria and unexplained episodes of lethargy and unconsciousness. The total excretion of adipic, suberic and sebacic acid ranged from 0.77 to 1.3 mg/mg creatinine after episodes of acute attack of the disease. Suberylglycine, identified by gas chromatography/mass spectrometry, was repeatedly found in the urine samples. The amount of this conjugate ranged from 0.2 to 0.5 mg/mg creatinine. The precursors of the dicarboxylic acids are suggested to be long chain monocarboxylic acids, oxidized through ω- and β-oxidation to adipic, suberic and sebacic acid. Suberylglycine is subsequently formed by glycine-N-acylase-catalyzed conjugation.

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In pathway analysis, high threonine and tyrosine levels could accelerate the oxidation of triglycerides and fatty acids [34]. Some intermediate metabolites involved in the incomplete fatty acid oxidation were also decreased, and they were decanoylcarnitine, L-octanoylcarnitine, nonanoylcarnitine, and suberylglycine [35–37]. Acetoacetate, a metabolite of fatty acid and a precursor of ketone bodies [38], could promote the generation of superoxide anion radicals and increase lipid peroxidation [39], and its high level has been reported when glucose oxidation is restricted [40].
The beneficial role of yogurt on metabolic profile has been widely reported. Yet, few studies have intended to describe the integrated metabolic alterations in response to yogurt. Yogurt and milk (220 g/d) were given to 48 and 44 obese women with metabolic syndrome and nonalcoholic fatty liver disease for 24 weeks in a randomized controlled trial (registered at http://www.chictr.org.cn as ChiCTR-IPR-15006801). Fasting serum samples were collected before and after intervention for global, untargeted metabolomics based on ¹H nuclear magnetic resonance (NMR) and ultra-high-performance liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry (UPLC-Q-TOF-MS) (in positive and negative ion modes). Multivariable statistical analysis and pathway analysis were conducted. In both ¹H NMR and UPLC-Q-TOF-MS metabolomics, no clustering was observed between the two groups at baseline. While, a clear clustering was shown after intervention, and the yogurt group had significantly different metabolic status from the milk. The metabolites that contributed mostly to class separation were identified, and involved into pathway analysis. Pathways on amino acids metabolism, fatty acid oxidation, cholesterol catabolism and choline metabolism significantly changed after yogurt intervention. The study revealed the integrated metabolic alterations in response to yogurt via two metabolomics approaches, suggesting the potential mechanisms of yogurt against metabolic disorders.
Chinese Clinical Trial Registry, ChiCTR-IPR-15006801. Registered 20 July 2015, http://www.chictr.org.cn/ ChiCTR-IPR-15006801.
Both review from prospective studies and our randomized clinical trial showed the protective role of yogurt against multiple metabolic disorders. However, they were focus on targeted glucose, lipid, and other metabolic indicators, which were only part of human metabolism, failing to show an integrated metabolic feature on yogurt. Therefore, two global, untargeted metabolomics were applied in our current randomized clinical trial, trying to uncover the significant metabolic alterations characterizing the effects of yogurt on obese women with multiple metabolic disorders, and to explore the potential biological mechanisms of yogurt. The finding will shed light on a more comprehensive picture of how yogurt affects host metabolism, and provide theoretical foundation for dietary prevention of chronic diseases.
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In suckling mammals, in contrast, the maternal milk represents a high-fat diet particularly rich in medium-chain fatty acids, which are actively synthesized by the mammary gland [11,12]. The importance of these substrates in the energy metabolism of the neonate was long unsuspected, until the first descriptions of fatal presentations of MCAD deficiency, in the 80's [13]. MCAD deficiency is now recognized as the most common FAO disorder in Caucasian populations.
The mitochondrial fatty acid β-oxidation (FAO) pathway plays a crucial role in ATP production in many tissues with high-energy demand. This is highlighted by the diverse and possibly severe clinical manifestations of inborn fatty acid β-oxidation deficiencies. More than fifteen genetic FAO enzyme defects have been described to date, forming a large group of rare diseases. Inborn FAO disorders are characterized by a high genetic heterogeneity, with a variety of gene mutations resulting in complete or partial loss-of-function of the corresponding enzyme. The panel of observed phenotypes varies from multi-organ failure in the neonate with fatal outcome, up to milder late onset manifestations associated with significant disabilities. Diagnosis of FAO disorders has markedly improved over the last decades, but few treatments are available. The clinical, biochemical, and molecular analysis of these disorders provided new, and sometimes unexpected, data on the organization and regulation of mitochondrial FAO in humans, in various tissues, and at various stages of development. This will be illustrated by examples of FAO defects affecting enzymes of long-chain fatty acid import into the mitochondria, or Lynen helix enzymes. The involvement of the transcriptional network regulating FAO gene expression, in particular the PGC-1α/PPAR axis, as a target for pharmacological therapy of these genetic disorders, will also be discussed.
MCAD deficiency in Denmark
2012, Molecular Genetics and Metabolism
Citation Excerpt :
In 1976 the first patient in Denmark and also in the world with medium-chain acyl-CoA dehydrogenase (MCAD; EC 1.3.99.3) deficiency (OMIM 201450) was described [1].
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS/MS), because MCADD is a frequent disease, and because of the success of early treatment initiated before clinical symptoms have emerged. In Denmark we have screened 519,350 newborns for MCADD by MS/MS and identified 58 affected babies. The diagnosis of MCADD was confirmed in all 58 newborns by mutation analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10 year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four times more newborns with MCADD are detected by screening than what is expected based on the number of children presenting clinically in an unscreened population.
The mutation spectrum in the newborns detected by screening is different from that observed in clinically presenting patients with a much lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated with a milder biochemical phenotype and may cause a milder form of MCADD with a relatively low risk of disease manifestation, thereby explaining part of the discrepancy between the frequency of clinically manifested MCADD and the frequency of MCADD determined by screening. In addition, our data suggest that some of this discrepancy can be explained by a reduced penetrance of the c.985A>G mutation, with perhaps only 50% of c.985A>G homozygotes presenting with disease manifestations.
Interestingly, we also report that the observed number of newborns identified by screening who are homozygous for the c.985A>G mutation is twice that predicted from the estimated carrier frequency. We therefore redetermined the carrier frequency in a new sample of 1946 blood spots using a new assay, but this only confirmed that the c.985A>G carrier frequency in Denmark is approximately 1/105.
We conclude that MCADD is much more frequent than expected, has a reduced penetrance and that rapid genotyping using the initial blood spot sample is important for correct diagnosis and counseling.
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2010, Molecular Genetics and Metabolism
Medium-chain acyl-coA dehydrogenase (MCAD) deficiency is a commonly detected fatty acid oxidation disorder and its diagnosis relies on both biochemical and molecular analyses. Over a 5-year period, sequencing all 12 exons of the MCAD gene (ACADM) in our laboratory revealed a total of 54 variants in 549 subjects analyzed. As most molecular ACADM testing is referred for the follow-up of an abnormal newborn screening result obtained from an asymptomatic newborn, the identification of a novel DNA variant, or “variant of unknown significance (VUS),” presents clinicians with a dilemma. Frequently, the results of molecular analyses are correlated to biochemical findings, such as the concentration of octanoylcarnitine (C8) in plasma and the excretion of hexanoylglycine (HG) in urine. Here, we describe the classification of genotypes harboring at least one VUS through the comparison of C8 and HG values measured in individuals who are carriers of, or affected with, MCAD deficiency on the basis of the following genotypes: c.985A>G/wildtype, c.199T>C/c.985A>G and c.985A>G/c.985A>G. Our findings emphasize the importance of obtaining both plasma and urine when following up positive newborn screening results and may influence the way physicians counsel their asymptomatic patients about MCAD deficiency after genetic analysis.
The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: Clinical presentation and outcome
2006, Journal of Pediatrics
To describe the clinical presentation and long-term follow-up of a large cohort of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
A nationwide, retrospective analysis of clinical presentation and follow-up in 155 Dutch patients with MCAD deficiency.
Most patients presented between 3 months and 5.1 years of age; 13% had symptoms as neonates not exclusively related to breast-feeding. An acute presentation before the diagnosis was made resulted in a mortality of 22% (25/114), whereas 21% (19/89) developed disabilities after the diagnosis. On follow-up, a total of 44 patients reported fatigue (35%; 28/80), muscle pain (31%; 25/80), and/or reduced exercise tolerance (39%; 31/80). Cardiac evaluation in 11 adult patients revealed no abnormalities in cardiac function explaining these complaints. Children with MCAD deficiency readily become overweight.
Mortality and morbidity were high in undiagnosed children with MCAD deficiency; establishment of the diagnosis significantly improves outcome. Strikingly, after the diagnosis and initiation of treatment, overweight and chronic complaints (fatigue, muscle pain, and reduced exercise tolerance) were prominent.
Genotypic differences of MCAD deficiency in the Asian population: Novel genotype and clinical symptoms preceding newborn screening notification
2005, Genetics in Medicine
Citation Excerpt :
Since its first report more than 25 years ago, medium-chain acyl-CoA dehydrogenase (MCAD; EC 1.3.99.3) deficiency (MIM 201450) has been recognized as the most commonly diagnosed fatty acid oxidation disorder.1,2
In contrast to its high prevalence in Caucasians, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is reported to be an extremely rare metabolic disorder in the Asian population. The common MCAD gene (ACADM) mutation 985A>G (p.K329E), accounting for the majority of cases in Caucasians, has not been detected in this ethnic group, and the spectrum of ACADM mutations has remained unknown.
Method: Biochemical genetic testing including plasma acylcarnitine and urine acylglycine analyses, as well as sequencing of ACADM was performed in a Korean family with a newborn who had an elevated octanoyl (C8) carnitine concentration by newborn screening (NBS). Genotyping of 50 Korean newborns with normal NBS results was performed.
Result: We report the identification of the first Korean patient with MCAD deficiency, caused by a novel missense mutation in ACADM, 843A>T (R281S), and a 4-bp deletion, c.449_452delCTGA. The patient became symptomatic before notification of the abnormal NBS result. Both the father and a brother who were identified as carriers for the 4-bp deletion had mildly elevated plasma C8 and C10:1 carnitine concentrations, whereas the acylcarnitine profile was normal in the mother who carries the missense mutation.
The 4-bp deletion may represent a common Asian ACADM mutation, considering that it recently has also been found in two of the three Japanese patients in whom genotyping was performed. Greater availability of MCAD mutation analysis is likely to unravel the molecular basis of MCAD deficiency in the Asian population that might differ from Caucasians.

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Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria

Abstract

J. Biol. Chem.

J. Pediatr.

Lancet

Lancet

J. Pediatr.

J. Pediatr.

Biochem. Med.

Bioehem. Med.

J. Chromatogr.

Clin. Chim. Acta

Clin. Chim. Acta

Clin. Chim. Acta

Clin. Chim. Acta