I N T R O D U C T I O NN X-linked cardioskeleta l myopathy and neutropeni a (Barth syndrome,, MIM 302060) is an X-linked recessiv e dilated cardiomyopathy , neutropeni a and skeletal myopathyy (1). Biochemical findings include variable mitochondrial respirator y chain dysfunctionn in skeletal muscl e and in cultured fibroblasts, increased urinary excretion of 3methylglutaconi cc acid, 3-methy-lglutari c acid, and 2-ethylhydracryli c acid and moderatel y decrease dd serum cholesterol . The gene involved in the disease is the Tafazzi n (TAZ) gene, whichh is localized on Xq28. Mutations have been identified in nearl y all Barth syndrome (BTHS)) patients. Inn 1997 Neuwal d (2) reported that the TAZ gene shares homology with acyltransferases ,, involved in phospholipi d biosynthesi s and/or remodeling, suggesting that a specific glycerophospholipi dd might be lacking in BTHS. We studied the biosynthesi s and remodeling off the phospholipids phosphatidylglycero l (PG) and cardiolipin, which are mainly confined too mitochondrial membranes , in cultured skin fibroblasts from BTHS patient s and controls. Thesee studies revealed reduced levels of CL and a disturbance in the remodeling of PG and CL.. In particular the incorporation of linoleic acid into PG and CL was dramaticall y reduced, whereass the incorporation of other fatty acids into these phospholipids was normal (3). Thesee studies proved defective remodeling of cardiolipin as a characteristi c and probabl y basicc disturbance in BTHS patients. The method however is laborious and involves incorporationn of radioactive labeled linoleic acid into skin fibroblasts. We therefore set out to

ATP-binding cassette (ABC) transporters facilitate unidirectional translocation of chemically diverse substances, ranging from peptides to lipids, across cell or organelle membranes. In peroxisomes, a subfamily of four ABC transporters (ABCD1 to ABCD4) has been related to fatty acid transport, because patients with mutations in ABCD1 (ALD gene) suffer from X-linked adrenoleukodystrophy (X-ALD), a disease characterized by an accumulation of very-long-chain fatty acids (VLCFAs). Inactivation in the mouse of the abcd1 gene leads to a late-onset neurodegenerative condition, comparable to the late-onset form of X-ALD [Pujol, A., Hindelang, C., Callizot, N., Bartsch, U., Schachner, M. and Mandel, J.L. (2002) Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum. Mol. Genet., 11, 499-505.]. In the present work, we have generated and characterized a mouse deficient for abcd2, the closest paralog to abcd1. The main pathological feature in abcd2-/- mice is a late-onset cerebellar and sensory ataxia, with loss of cerebellar Purkinje cells and dorsal root ganglia cell degeneration, correlating with accumulation of VLCFAs in the latter cellular population. Axonal degeneration was present in dorsal and ventral columns in spinal cord. We have identified mitochondrial, Golgi and endoplasmic reticulum damage as the underlying pathological mechanism, thus providing evidence of a disturbed organelle cross-talk, which may be at the origin of the pathological cascade.

Objective. To understand the expanding clinical and biochemical spectrum of short-chain acyl-CoA dehydrogenase (SCAD) deficiency, the impact of which is not fully understood. Study Design. We studied a family with SCAD deficiency and determined urinary ethylmalonic acid excretion, plasma C4-carnitine, SCAD enzyme activity in fibroblasts and lymphocytes, DNA mutations in the SCAD gene, and clinical expression. The index patient was born prematurely and had otherwise unexplained cholestasis and hepatomegaly during the first year of life. His mother developed a hemolysis-elevated liver enzymes-low platelets (HELLP) syndrome while pregnant with the index patient. Results. Two siblings had a homozygous inactivating 1138C>T mutation, whereas the father was compound heterozygous for this mutation and the common 625G>A polymorphism. There was a good correlation between the type of SCAD mutation, the residual SCAD enzyme activity, and the levels of urinary ethylmalonic acid and plasma C4-carnitine in each of the eight family members. Retrospective acylcarnitine analysis of the index patient’s Guthrie screening card confirmed the abnormal increase of C4-carnitine, suggestive of SCAD deficiency. None of the family members had hypotonia, developmental delay, or episodes of ketotic hypoglycemia. Conclusion. Homozygosity for an inactivating SCAD mutation does not necessarily result in disease. The previously held opinion that SCAD deficiency is always a serious disorder may have been influenced by a clinical bias. Homozygosity for an inactivating 1138C>T SCAD mutation was assessed by neonatal screening of blood spot acylcarnitines. SCAD deficiency may be associated with maternal HELLP syndrome.

Plasma and erythrocyte fatty acids have been measured in 9 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency being treated with a low-fat diet. No significant abnormality was detected and in particular docosahexaenoic acid was not deficient.

Cardiomyopathy is common in infants with long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency. Resolution of the cardiomyopathy can often be achieved by avoidance of fasting and changing from a conventional infant formula to one in which most long-chain fat is replaced by medium-chain triglycerides (MCT). It is uncertain whether the clinical improvement is due to the restriction of long-chain fat or whether the MCT have specific beneficial effects. To clarify this, the metabolic effects of MCT were examined in 5 patients. When given at around the level found in MCT-based infant formula, MCT had no effect on blood concentrations of ketone bodies, specific fatty acids or acylcarnitines. The present study cannot, however, exclude the possibility that MCT per se may have beneficial effects.

In X-linked adrenoleukodystrophy (X-ALD) the peroxisomal ß-oxidation of saturated very long chain fatty acids (VLCFA-carbon length >22 atoms) is impaired. These fatty acids accumulate in blood and tissues, in particular in the nervous system, adrenal cortex and testes. Most patients have a primary adrenocortical insufficiency with low levels of Cortisol and dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) collectively called DHEA(S). Surprisingly, very low plasma levels of DHEA(S) may be found when plasma Cortisol and ACTH levels are still normal (Assies et al 1998). In animal studies DHEA-administration had a peroxisome proliferator effect and induced the expression of peroxisomal enzymes involved in the ß-oxidation of fatty acids (Waxman,1996, Depreter et al.). To study the effect of DHEA on fatty acids in X-ALD patients we conducted a randomised double blind study in which fourteen men, age range 21-63 years and one boy (12 year), received 50 mg of DHEA or placebo for 3 months, followed by a one month wash-out period, then 3 month of placebo or vice versa.

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Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid derived from dietary sources and broken down in the peroxisome to pristanic acid (2,6,10,14-tetramethylpentadecanoic acid) via alpha-oxidation. Pristanic acid then undergoes beta-oxidation in peroxisomes. Phytanic acid naturally occurs as a mixture of (3S,7R, 11R)and (3R, 7R, 11R)-diastereomers. In contrast to the alpha-oxidation system, peroxisomal beta-oxidation is stereospecific and only accepts (2S)-isomers. Therefore, a racemase called alpha-methylacyl-CoA racemase is required to convert (2R)-pristanic acid into its (2S)-isomer. To further investigate the stereochemistry of the peroxisomal oxidation systems and their substrates, we have developed a method using gas-liquid chromatography-mass spectrometry to analyze the isomers of phytanic, pristanic, and trimethylundecanoic acid in plasma from patients with various peroxisomal. fatty acid oxidation defects. In this study, we show that in plasma of patients, with a peroxisomal beta-oxidation deficiency, the relative amounts of the two diastereomers of pristanic acid are almost equal, whereas in patients with a defect of alpha-methylacyl-CoA racemase, (2R)-pristanic acid is the predominant isomer. Furthermore, we show that in alpha-methylacyl-CoA racemase deficiency, not only pristanic acid accumulates, but also one of the metabolites of pristanic acid, (2,6,10)trimethylundecanoic acid, providing direct in vivo evidence for the requirement of this racemase for the complete degradation of pristanic acid.

X-linked cardioskeletal myopathy, neutropenia and abnormal mitochondria (MIM 302060) (synonyms: Barth syndrome, 3-methylglutaconic aciduria type II, endocardial fibroelastosis type 2) has been reported in patients and families from Europe, North America and Australia. Previous studies characterized the main components of the disease: dilated cardiomyopathy, skeletal myopathy, neutropenia, 3-methylglutaconic aciduria and diminished statural growth. Respiratory chain impairments have been found in several studies, without pinpointing a single enzyme complex. 3-Methylglutaconic aciduria is shared with several other disorders that affect the respiratory chain. Previous studies excluded a block in the major pathway of leucine catabolism. We performed leucine loading, accompanied by fasting, in patients and observed a significant rise of 3-methylglutaconic acid and 3-methylglutaric acid. Taken together with the absence of an enzymatic block in the major leucine catabolic route, the possibility remains that the increased basal excretion of 3-methylglutaconic acid and other products of branched-chain amino acids is the result of overload of this pathway or — more likely — mitochondrial leakage. Linkage studies have localized the gene to the Xq28 region. The associated tafazzin gene (TAZ), has been fully characterized recently, and mutations located in conserved regions have been reported. Carrier detection and prenatal diagnosis have now become possible through mutation analysis. Sequence homology of the TAZ gene to a highly conserved superclass of acyltransferases (Neuwald's hypothesis) predicts a glycerophospholipid as the missing end product. This points to the (lipid) structure of the inner mitochondrial membrane as a promising new area of research.

Objectives To determine if bilateral salpingo-oophorectomy, compared with ovarian conservation, is associated with all cause or cause specific death in women undergoing hysterectomy for non-malignant disease, and to determine how this association varies with age at surgery. Design Population based cohort study. Setting Ontario, Canada from 1 January 1996 to 31 December 2015, and follow-up to 31 December 2017. Participants 200 549 women (aged 30-70 years) undergoing non-malignant hysterectomy, stratified into premenopausal (<45 years), menopausal transition (45-49 years), early menopausal (50-54 years), and late menopausal (≥55 years) groups according to age at surgery; median follow-up was 12 years (interquartile range 7-17). Exposures Bilateral salpingo-oophorectomy versus ovarian conservation. Main outcomes measures The primary outcome was all cause death. Secondary outcomes were non-cancer and cancer death. Within each age group, overlap propensity score weighted survival models were used to examine the association between bilateral salpingo-oophorectomy and mortality outcomes, while adjusting for demographic characteristics, gynaecological conditions, and comorbidities. To account for comparisons in four age groups, P<0.0125 was considered statistically significant. Results Bilateral salpingo-oophorectomy was performed in 19%, 41%, 69%, and 81% of women aged <45, 45-49, 50-54, and ≥55 years, respectively. The procedure was associated with increased rates of all cause death in women aged <45 years (hazard ratio 1.31, 95% confidence interval 1.18 to 1.45, P<0.001; number needed to harm 71 at 20 years) and 45-49 years (1.16, 1.04 to 1.30, P=0.007; 152 at 20 years), but not in women aged 50-54 years (0.83, 0.72 to 0.97, P=0.018) or ≥55 years (0.92, 0.82 to 1.03, P=0.16). Findings in women aged <50 years were driven largely by increased non-cancer death. In secondary analyses identifying a possible change in the association between bilateral salpingo-oophorectomy and all cause death with advancing age at surgery, the hazard ratio gradually decreased during the menopausal transition and remained around 1 at all ages thereafter. Conclusion In this observational study, bilateral salpingo-oophorectomy at non-malignant hysterectomy appeared to be associated with increased all cause mortality in women aged <50 years, but not in those aged ≥50 years. While caution is warranted when considering bilateral salpingo-oophorectomy in premenopausal women without indication, this strategy for ovarian cancer risk reduction does not appear to be detrimental to survival in postmenopausal women.

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BACKGROUND:We developed a method to determine the urinary concentrations of metabolites in the synthetic pathway for carnitine from N(6)-trimethyllysine and applied this method to determine their excretion in control individuals. In addition, we investigated whether newborns are capable of carnitine synthesis from deuterium-labeled N(6)-trimethyllysine.METHODS:Urine samples were first derivatized with methyl chloroformate. Subsequently, the analytes were separated by ion-pair, reversed-phase HPLC and detected online by electrospray tandem mass spectrometry. Stable-isotope-labeled reference compounds were used as internal standards.RESULTS:The method quantified all carnitine biosynthesis metabolites except 4-N-trimethylaminobutyraldehyde. Detection limits were 0.05-0.1 micromol/L. The interassay imprecision (CV) for urine samples with added compounds was 6-12%. The intraassay imprecision (CV) was 1-5% (3-10 micromol/L). Recoveries were 94-106% at 10-20 micromol/L and 98-103% at 100-200 micromol/L. The mean (SD) excretions of N(6)-trimethyllysine and 3-hydroxy-N(6)-trimethyllysine were 2.8 (0.8) and 0.45 (0.15) mmol/mol creatinine, respectively. gamma-Butyrobetaine and carnitine excretions were more variable with values of 0.27 (0.21) and 15 (12) mmol/mol creatinine, respectively. After oral administration of deuterium-labeled N(6)-trimethyllysine, all urines of newborns contained deuterium-labeled N(6)-trimethyllysine, 3-hydroxy-N(6)-trimethyllysine, gamma-butyrobetaine, and carnitine.CONCLUSIONS:HPLC in combination with electrospray ionization tandem mass spectrometry allows rapid determination of urinary carnitine biosynthesis metabolites. Newborns can synthesize carnitine from exogenous N(6)-trimethyllysine, albeit at a low rate.

Background: Fatty acid research in schizophrenia has demonstrated an altered cell membrane phospholipid metabolism. Erythrocyte membrane phospholipid composition closest reflects that of neuronal membranes.Methods: (Poly)(un)saturated fatty acid concentrations were measured in the erythrocyte membranes of 19, consecutively admitted, medicated young schizophrenic patients and then compared with matched control subjects. Psychiatric symptomatology was rated with the Positive and Negative Symptom Scale and Montgomery-Asberg Depression Rating Scale. Because diet, hormones, and cannnbis influence fatty acid metabolism, we included these factors in our study.Results: The most distinctive findings concerned the omega -3 series: C22:5 omega -3, C22:6 omega -3 (docosahexaenoic acid), and the sum of omega -3 fatty acids were significantly decreased. Interestingly, C20:4 omega -6 (arachidonic acid) was not lowered. In the omega -9 series, higher levels of C22:1 omega -9 and lower levels its elongation product, C24:1 omega -9 (nervonic acid), were found. Interestingly the other arm of the desaturarion-elongation sequence of C18:1 omega -9, C20, 3 omega -9, was lower in patients. The total omega -9 fatty acid levels were also lower in patients.Conclusions: Significant differences in erythrocyte fatty acid composition were found. The differences were not due to diet or hormonal status and could not be explained by the medication or cannabis use. No consistent pattern emerged from the different fatty acid abnormalities and the clinical symptom scores. Biol Psychiatry 2001;49: 510-522 (C) 2001 Society of Biological Psychiatry.

Conference Abstract| February 01 2001 Plasma analysis of di- and trihydroxycholestanoic acid (DHCA and THCA) stereoisomers using HPLC tandem mass spectrometry and its application in peroxisomal alpha-methylacyl-CoA racemase deficiency S Ferdinandusse; S Ferdinandusse 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar H Overmars; H Overmars 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar S Denis; S Denis 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar HR Waterham; HR Waterham 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar RJA Wanders; RJA Wanders 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar P Vreken P Vreken 1Academic Medical Center, University of Amsterdam, Dept. of Clinical Chemistry and Div. Emma Children's Hospital, FO-224, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (2001) 29 (1): A27. https://doi.org/10.1042/bst029a027 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation S Ferdinandusse, H Overmars, S Denis, HR Waterham, RJA Wanders, P Vreken; Plasma analysis of di- and trihydroxycholestanoic acid (DHCA and THCA) stereoisomers using HPLC tandem mass spectrometry and its application in peroxisomal alpha-methylacyl-CoA racemase deficiency. Biochem Soc Trans 1 February 2001; 29 (1): A27. doi: https://doi.org/10.1042/bst029a027 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 2001 Biochemical Society2001 Article PDF first page preview Close Modal You do not currently have access to this content.

Two new individuals with α-NAGA deficiency are presented. The index patient, 3 years old, has congenital cataract, slight motor retardation and secondary demyelinisation. Screening of his sibs revealed an α-NAGA deficiency in his 7-year-old healthy brother who had no clinical or neurological symptoms. Both sibs are homozygous for the E325K mutation, the same genotype that was found in the most severe form of α-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of α-NAGA may present as a ‘non-disease’ (present healthy case) and can be associated with the vegetative state (the first two patients described with α-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with α-NAGA deficiency is extreme, with a ‘non-disease’ (two cases) and infantile neuroaxonal dystrophy (two cases) at the opposite sides of the clinical spectrum. The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have angiokeratoma and clear vacuolisation in various cell types (three cases). These observations are difficult to reconcile with a straightforward genotype-phenotype correlation and suggest that factors or genes other than α-NAGA contribute to the clinical heterogeneity of the 11 patients with α-NAGA deficiency.

Journal of Inherited Metabolic DiseaseVolume 24, Issue 3 p. 421-422 Article Carnitine-responsive carnitine insufficiency in a case of mtDNA 8993T>C mutation associated Leigh syndrome G. Tóth, G. Tóth Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorÉ. Morava, É. Morava Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorJ. Bene, J. Bene Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorJ. J. M. Selhorst, J. J. M. Selhorst Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorH. Overmars, H. Overmars Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorP. Vreken, P. Vreken Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorJ. Molnár, J. Molnár National Institute of Psychiatry and Neurology, BudapestSearch for more papers by this authorV. Farkas, V. Farkas 1st Department of Pediatrics, Semmelweis University, Budapest, HungarySearch for more papers by this authorB. Melegh, Corresponding Author B. Melegh Bela.Melegh@aok.pte.hu Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungaryBela.Melegh@aok.pte.huSearch for more papers by this author G. Tóth, G. Tóth Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorÉ. Morava, É. Morava Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorJ. Bene, J. Bene Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungarySearch for more papers by this authorJ. J. M. Selhorst, J. J. M. Selhorst Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorH. Overmars, H. Overmars Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorP. Vreken, P. Vreken Academic Medical Center, Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorJ. Molnár, J. Molnár National Institute of Psychiatry and Neurology, BudapestSearch for more papers by this authorV. Farkas, V. Farkas 1st Department of Pediatrics, Semmelweis University, Budapest, HungarySearch for more papers by this authorB. Melegh, Corresponding Author B. Melegh Bela.Melegh@aok.pte.hu Department of Medical Genetics and Child Development, University of Pécs, Pécs, HungaryBela.Melegh@aok.pte.huSearch for more papers by this author First published: 01 June 2001 https://doi.org/10.1023/A:1010537527291Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume24, Issue3June 2001Pages 421-422 RelatedInformation

In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, β‐ureidopropionase (UP) deficiency, are reported. 1D 1 H‐NMR experiments were performed using a patient's urine. 3‐Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D 1 H‐ 1 H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single‐quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3‐ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D 1 H‐NMR spectroscopy, UP deficiency can be easily diagnosed. The 1 H‐NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway. Magn Reson Med 46:1014–1017, 2001. © 2001 Wiley‐Liss, Inc.

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