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Victoria M Pak, Feng Dai, Brendan T Keenan, Nalaka S Gooneratne, Allan I Pack
Sleepiness and cardiovascular disease share common molecular pathways; thus, metabolic risk factors for sleepiness may also predict cardiovascular disease risk. Daytime sleepiness predicts mortality and cardiovascular disease, although the mechanism is unidentified. This study explored the associations between subjective sleepiness and metabolite concentrations in human blood plasma within the oxidative and inflammatory pathways, in order to identify mechanisms that may contribute to sleepiness and cardiovascular disease risk...
April 2018: Sleep Medicine
Karit Reinson, Kadi Künnapas, Annika Kriisa, Mari-Anne Vals, Kai Muru, Katrin Õunap
Vitamin B12 deficiency seems to be more common worldwide than previously thought. However, only a few reports based on data from newborn screening (NBS) programs have drawn attention to that subject. In Estonia, over the past three years, we have diagnosed 14 newborns with congenital acquired vitamin B12 deficiency. Therefore, the incidence of that condition is 33.8/100,000 live births, which is considerably more than previously believed. None of the newborns had any clinical symptoms associated with vitamin B12 deficiency before the treatment, and all biochemical markers normalized after treatment, which strongly supports the presence of treatable congenital deficiency of vitamin B12...
June 2018: Molecular Genetics and Metabolism Reports
Austin A Larson, Shanti Balasubramaniam, John Christodoulou, Lindsay C Burrage, Ronit Marom, Brett H Graham, George A Diaz, Emma Glamuzina, Natalie Hauser, Bryce Heese, Gabriella Horvath, Andre Mattman, Clara van Karnebeek, S Lane Rutledge, Amy Williamson, Lissette Estrella, Johan K L van Hove, James D Weisfeld-Adams
Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m...
January 4, 2018: Mitochondrion
Ferenc Papp, Gábor Rácz, István Lénárt, Jenő Kóbor, Csaba Bereczki, Eszter Karg, Ákos Baráth
INTRODUCTION: Infant vitamin B12 deficiency can manifest as a severe neurodegenerative disorder and is usually caused by maternal deficiency due to vegetarian diet or pernicious anaemia. Its early recognition and treatment can prevent potentially serious and irreversible neurologic damage. Biochemically, vitamin B12 deficiency leads to an accumulation of methylmalonic acid, homocysteine, and propionylcarnitine. Expanded newborn screening using tandem mass spectrometry may identify neonatal and maternal vitamin B12 deficiency by measurement of propionylcarnitine and other metabolites in the dried blood spot sample of newborns...
December 2017: Orvosi Hetilap
Lili Yang, Yu Zhang, Jianbin Yang, Xinwen Huang
Background Birth weight influences profiles of dried blood amino-acids and acylcarnitines in newborn screening. This study aimed to define a more appropriate cut-off value to reduce the false positive rate and the number of recalled patients in newborn screening. Methods All babies who underwent newborn screening in our center were included; they were divided into groups by birth weight: 2500-3999 g (comparator group), <1000 g (group 1), 1000-1499 g (group 2), 1500-2499 g (group 3), and >4000 g (group 4)...
January 1, 2017: Annals of Clinical Biochemistry
Péter Monostori, Glynis Klinke, Sylvia Richter, Ákos Baráth, Ralph Fingerhut, Matthias R Baumgartner, Stefan Kölker, Georg F Hoffmann, Gwendolyn Gramer, Jürgen G Okun
BACKGROUND AND AIMS: Increased propionylcarnitine levels in newborn screening are indicative for a group of potentially severe disorders including propionic acidemia (PA), methylmalonic acidemias and combined remethylation disorders (MMACBL). This alteration is relatively non-specific, resulting in the necessity of confirmation and differential diagnosis in subsequent tests. Thus, we aimed to develop a multiplex approach for concurrent determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid from the same dried blood spot (DBS) as in primary screening (second-tier test)...
2017: PloS One
Mohamad Hafizi Abu Bakar, Mohamad Roji Sarmidi
Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor...
August 22, 2017: Molecular BioSystems
Joo Ern Ang, Akos Pal, Yasmin J Asad, Alan T Henley, Melanie Valenti, Gary Box, Alexis de Haven Brandon, Victoria Revell, Debra J Skene, Miro Venturi, Ruediger Rueger, Valerie Meresse, Suzanne A Eccles, Johann S de Bono, Stanley B Kaye, Paul Workman, Udai Banerji, Florence I Raynaud
<p>MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines and sphingomyelins that were significantly altered in two B-RAF mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655...
June 21, 2017: Molecular Cancer Therapeutics
William Cheung, Pekka Keski-Rahkonen, Nada Assi, Pietro Ferrari, Heinz Freisling, Sabina Rinaldi, Nadia Slimani, Raul Zamora-Ros, Milena Rundle, Gary Frost, Helena Gibbons, Eibhlin Carr, Lorraine Brennan, Amanda J Cross, Valeria Pala, Salvatore Panico, Carlotta Sacerdote, Domenico Palli, Rosario Tumino, Tilman Kühn, Rudolf Kaaks, Heiner Boeing, Anna Floegel, Francesca Mancini, Marie-Christine Boutron-Ruault, Laura Baglietto, Antonia Trichopoulou, Androniki Naska, Philippos Orfanos, Augustin Scalbert
Background: Meat and fish intakes have been associated with various chronic diseases. The use of specific biomarkers may help to assess meat and fish intake and improve subject classification according to the amount and type of meat or fish consumed.Objective: A metabolomic approach was applied to search for biomarkers of meat and fish intake in a dietary intervention study and in free-living subjects from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.Design: In the dietary intervention study, 4 groups of 10 subjects consumed increasing quantities of chicken, red meat, processed meat, and fish over 3 successive weeks...
March 2017: American Journal of Clinical Nutrition
Lian-Shu Han, Zhuo Huang, Feng Han, Yu Wang, Zhu-Wen Gong, Xue-Fan Gu
BACKGROUND: Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT). This study aimed to verify whether missense mutations in MUT in Chinese patients affect the stability and enzymatic activity of MCM. METHODS: Eight Chinese patients were identified with novel mutations. Plasmids carrying the wild-type and mutated MUT cDNA were constructed and transfected into HEK293T cells for functional analyses...
January 19, 2017: World Journal of Pediatrics: WJP
Gwendolyn Gramer, Ghassan Abdoh, Tawfeg Ben-Omran, Noora Shahbeck, Rehab Ali, Laila Mahmoud, Junmin Fang-Hoffmann, Georg F Hoffmann, Hilal Al Rifai, Jürgen G Okun
BACKGROUND: Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-ß-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar. METHODS: A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine-ratio and propionylcarnitine as second-tiers...
April 2017: World Journal of Pediatrics: WJP
Gerarda Cappuccio, Paldeep S Atwal, Taraka R Donti, Kiki Ugarte, Nadia Merchant, William J Craigen, V Reid Sutton, Sarah H Elsea
We report three patients with elevations of propionylcarnitine (C3), one without elevations of 2-methylcitrate and 3-hydroxypropionate in urine organic acid analysis, and the other two showing only mild elevations, all of whom were subsequently confirmed to have propionic acidemia by molecular analysis of PCCA and PCCB genes. To date, they have had a mild clinical course. These cases illustrate the importance of considering high C3 as the only biochemical abnormality in a diagnosis of propionic acidemia. Since mild C3 elevations may be overlooked and considered non-diagnostic in isolation, we advise considering a diagnosis of propionic acidemia even in the absence of significant elevations 2-methylcitrate or 3-hydroxypropionate in urine organic acid analysis...
2017: JIMD Reports
Paula J Waters, Fanny Thuriot, Joe T R Clarke, Serge Gravel, David Watkins, David S Rosenblatt, Sébastien Lévesque
Methylmalonyl-coA epimerase (MCE) follows propionyl-coA carboxylase and precedes methylmalonyl-coA mutase in the pathway converting propionyl-coA to succinyl-coA. MCE deficiency has previously been described in six patients, one presenting with metabolic acidosis, the others with nonspecific neurological symptoms or asymptomatic. The clinical significance and biochemical characteristics of this rare condition have been incompletely defined. We now describe a patient who presented acutely at 5 years of age with vomiting, dehydration, confusion, severe metabolic acidosis and mild hyperammonemia...
December 2016: Molecular Genetics and Metabolism Reports
Somayeh Ahmadloo, Saeed Talebi, Mohammad Miryounesi, Parvin Pasalar, Mohammad Keramatipour
OBJECTIVE: Methylmalonic acidura (MMA) is a rare autosomal recessive inborn error of metabolism. In this study we present a novel nucleotide change in the mutase (MUT) gene of two unrelated Iranian pedigrees and introduce the methods used for its functional analysis. MATERIALS AND METHODS: Two probands with definite diagnosis of MMA and a common novel variant in the MUT were included in a descriptive study. Bioinformatic prediction of the splicing variant was done with different prediction servers...
2016: Cell Journal
Patrick Forny, Anke Schumann, Merima Mustedanagic, Déborah Mathis, Marie-Angela Wulf, Nadine Nägele, Claus-Dieter Langhans, Assem Zhakupova, Joerg Heeren, Ludger Scheja, Ralph Fingerhut, Heidi L Peters, Thorsten Hornemann, Beat Thony, Stefan Kölker, Patricie Burda, D Sean Froese, Olivier Devuyst, Matthias R Baumgartner
Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects...
September 23, 2016: Journal of Biological Chemistry
Shanti Balasubramaniam, B Lewis, D M Mock, H M Said, M Tarailo-Graovac, A Mattman, C D van Karnebeek, D R Thorburn, R J Rodenburg, J Christodoulou
Leigh syndrome (LS), or subacute necrotizing encephalomyelopathy, is a genetically heterogeneous, relentlessly progressive, devastating neurodegenerative disorder that usually presents in infancy or early childhood. A diagnosis of Leigh-like syndrome may be considered in individuals who do not fulfil the stringent diagnostic criteria but have features resembling Leigh syndrome.We describe a unique presentation of Leigh-like syndrome in a 3-year-old boy with elevated 3-hydroxyisovalerylcarnitine (C5-OH) on newborn screening (NBS)...
2017: JIMD Reports
Cynthia Roy, Pierre-Yves Tremblay, Jean-François Bienvenu, Pierre Ayotte
Metabolomics is an "omic" technique being increasingly used in epidemiological and clinical studies. We developed a method combining untargeted metabolomics with the quantitative determination of eight amino acids (AA) and eight acylcarnitines (AC) in plasma using ultra-high pressure liquid chromatography (UHPLC), electrospray ionization (ESI) and quadrupole time-of-flight mass spectrometry (QTOFMS). Separation of metabolites is performed by ion-pair reverse phase UHPLC using a HSS T3 column (2.1×100mm, 100Å, 1...
August 1, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Osama Y Al-Dirbashi, Nathan McIntosh, Pranesh Chakraborty
Background Newborn screening for propionic acidemia and methylmalonic acidurias using the marker propionylcarnitine (C3) is neither sensitive nor specific. Using C3 to acetylcarnitine (C3/C2) ratio, together with conservative C3 cut-offs, can improve screening sensitivity, but the false positive rate remains high. Incorporating the marker 2-methylcitric acid has been suggested, to improve the positive predictive value for these disorders without compromising the sensitivity. Methods Between July 2011 and December 2012 at the Newborn Screening Ontario laboratory, all neonatal dried blood spot samples that were reported as screen positive for propionic acidemia or methylmalonic acidurias based on elevated C3 and C3/C2 ratio were analyzed for 2-methylcitric acid, using liquid chromatography tandem mass spectrometry...
June 2017: Journal of Medical Screening
Xiang Gao, Weidong Zhang, Yongbo Wang, Pardis Pedram, Farrell Cahill, Guangju Zhai, Edward Randell, Wayne Gulliver, Guang Sun
BACKGROUND: Metabolic abnormalities are more associated with central obesity than peripheral obesity, but the underlying mechanisms are largely unknown. The present study was to identify serum metabolic biomarkers which distinguish metabolically unhealthy centrally obese (MUCO) from metabolically healthy peripherally obese (MHPO) individuals. METHODS: A two-stage case-control study design was employed. In the discovery stage, 20 individuals (10 MHPO and 10 MUCO) were included and in the following validation stage, 79 individuals (20 normal weight (NW), 30 MHPO, 29 MUCO) were utilized...
2016: Nutrition & Metabolism
Y P Liu, X Y Li, Y Ding, Q Wang, J Q Song, Y Zhang, D X Li, Y P Qin, Y L Yang
OBJECTIVE: To study the clinical and genetic features of the patients with secondary methylmalonic aciduria due to succinate-CoA ligase deficiency. METHOD: From February 2011 to April 2014, 4 Chinese patients with succinate-CoA ligase deficiency and mild methylmalonic aciduria were enrolled in this study. The clinical course, biochemical features, brain MRI findings, and mutations were analyzed. RESULT: Four patients presented with severe psychomotor retardation, hypotonia, seizures, feeding problems and failure to thrive from the age of one day to 6 months...
May 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
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