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Molecular Genetics and Metabolism

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https://www.readbyqxmd.com/read/28412083/elucidation-of-the-complex-metabolic-profile-of-cerebrospinal-fluid-using-an-untargeted-biochemical-profiling-assay
#1
Adam D Kennedy, Kirk L Pappan, Taraka R Donti, Anne M Evans, Jacob E Wulff, Luke A D Miller, V Reid Sutton, Qin Sun, Marcus J Miller, Sarah H Elsea
We sought to determine the molecular composition of human cerebrospinal fluid (CSF) and identify the biochemical pathways represented in CSF to understand the potential for untargeted screening of inborn errors of metabolism (IEMs). Biochemical profiles for each sample were obtained using an integrated metabolomics workflow comprised of four chromatographic techniques followed by mass spectrometry. Secondarily, we wanted to compare the biochemical profile of CSF with those of plasma and urine within the integrated mass spectrometric-based metabolomic workflow...
April 9, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28410878/efficacy-of-laronidase-therapy-in-patients-with-mucopolysaccharidosis-type-i-who-initiated-enzyme-replacement-therapy-in-adult-age-a-systematic-review-and-meta-analysis
#2
Jordi Pérez-López, Montserrat Morales-Conejo, Mónica López-Rodríguez, Álvaro Hermida-Ameijeiras, Marc Moltó-Abad
BACKGROUND: The efficacy of starting enzyme replacement therapy (ERT) in adults with Muchopolysaccharidosis Type I (MPS-I) is controversial. Evaluating the benefits reported by patients initiating ERT with laronidase at adult age might help physicians decide whether the use of ERT in these patients is worthwhile from a clinical point of view. OBJECTIVE: To assess every effectiveness variable modified in MPS-I patients who initiated laronidase at adult age. METHODS: A systematic search of the literature, from inception to July 2016, was conducted using MEDLINE, EMBASE, CENTRAL and LILACS to identify randomized trials or observational studies including ≥1 MPS-I patients with ERT initiated in adult age (≥18years) and evaluating ERT efficacy...
April 9, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28400091/metabolomic-changes-demonstrate-reduced-bioavailability-of-tyrosine-and-altered-metabolism-of-tryptophan-via-the-kynurenine-pathway-with-ingestion-of-medical-foods-in-phenylketonuria
#3
Denise M Ney, Sangita G Murali, Bridget M Stroup, Nivedita Nair, Emily A Sawin, Fran Rohr, Harvey L Levy
BACKGROUND: Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). METHODS: Subjects with PKU consumed a low-Phe diet combined with AA-MF or GMP-MF for 3weeks each in a randomized, controlled, crossover study...
April 6, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28410879/determination-of-reference-genes-that-are-independent-of-feeding-rhythms-for-circadian-studies-of-mouse-metabolic-tissues
#4
Reiko Nakao, Hiroki Okauchi, Chiaki Hashimoto, Naoyuki Wada, Katsutaka Oishi
Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is a popular method for the measurement of mRNA expression level and is a critical tool for basic research. The identification of suitable reference genes that are stable and not affected by experimental conditions is a critical step in the accurate normalization of RT-PCR. On the other hand, the levels of numerous transcripts exhibit circadian oscillation in various peripheral tissues and it is thought to be regulated by feeding rhythms in addition to the molecular circadian clock...
April 5, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28391974/generation-of-induced-pluripotent-stem-cells-as-disease-modelling-of-nlsdm
#5
D Tavian, S Missaglia, M Castagnetta, D Degiorgio, E M Pennisi, R A Coleman, P Dell'Era, C Mora, C Angelini, D A Coviello
Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids...
April 3, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28385533/molecular-analysis-of-sequence-and-splice-variants-of-the-human-slc13a4-sulfate-transporter
#6
Zhe Zhang, Zin Thu Aung, David G Simmons, Paul A Dawson
The solute linked carrier 13A4 gene (SLC13A4) is abundantly expressed in the human and mouse placenta where it is proposed to transport nutrient sulfate to the fetus. In mice, targeted disruption of placental Slc13a4 leads to severe and lethal fetal phenotypes, however the involvement of SLC13A4 in human development is unknown. A search of the NCBI and Ensembl gene databases identified two alternatively spliced SLC13A4 mRNA transcripts and 98 SLC13A4 gene variants, including 85 missense, 4 splice site, 5 frameshift and 2 nonsense variants, as well as 2 in-frame deletions...
April 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28396157/coupled-brain-and-urine-spectroscopy-in-vivo-metabolomic-characterization-of-hmg-coa-lyase-deficiency-in-5-patients
#7
Dominique Roland, Patrice Jissendi-Tchofo, Gilbert Briand, Joseph Vamecq, Monique Fontaine, Vincent Ultré, Cécile Acquaviva-Bourdain, Karine Mention, Dries Dobbelaere
BACKGROUND: 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) lyase deficiency is a rare inborn error of leucine metabolism and ketogenesis. Despite recurrent hypoglycemia and metabolic decompensations, most patients have a good clinical and neurological outcome contrasting with abnormal brain magnetic resonance imaging (MRI) signals and consistent abnormal brain proton magnetic resonance spectroscopy ((1)H-MRS) metabolite peaks. Identifying these metabolites could provide surrogate markers of the disease and improve understanding of MRI-clinical discrepancy and follow-up of affected patients...
March 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28377240/next-generation-sequencing-of-the-monogenic-obesity-genes-lep-lepr-mc4r-pcsk1-and-pomc-in-a-norwegian-cohort-of-patients-with-morbid-obesity-and-normal-weight-controls
#8
Gry B N Nordang, Øyvind L Busk, Kristian Tveten, Hans Ivar Hanevik, Anne Kristin M Fell, Jøran Hjelmesæth, Øystein L Holla, Jens K Hertel
BACKGROUND: Rare sequence variants in at least five genes are known to cause monogenic obesity. In this study we aimed to investigate the prevalence of, and characterize, rare coding and splice site variants in LEP, LEPR, MC4R, PCSK1 and POMC in patients with morbid obesity and normal weight controls. METHOD: Targeted next-generation sequencing of all exons in LEP, LEPR, MC4R, PCSK1 and POMC was performed in 485 patients with morbid obesity and 327 normal weight population-based controls from Norway...
March 29, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28377241/genetic-epidemiological-study-doesn-t-support-gla-ivs4-919g-a-variant-is-a-significant-mutation-in-fabry-disease
#9
Hung-Lun Chiang, Nana Hsiang-Hua Wang, I-Wen Song, Chun-Ping Chang, Ming-Shien Wen, Yin-Hsiu Chien, Wuh-Liang Hwu, Fuu-Jen Tsai, Yuan-Tsong Chen, Jer-Yuarn Wu
BACKGROUND: The GLA IVS4+919G>A which is linked to late-onset Fabry disease shows high frequency in Taiwan. METHODS: To determine whether IVS4+919G>A is a frequent cause of heart disease, we genotyped it in normal controls and other disease cohorts (type 2 diabetes, heart failure, ventricular tachycardia, atrial fibrillation and coronary artery disease). Normal controls and diabetes patients carrying the variant were evaluated for their cardiac condition. Minigene constructs were used to study GLA splicing patterns in different cell lines...
March 24, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28385534/type-2-diabetes-associated-variants-with-cross-trait-relevance-post-gwas-strategies-for-biological-function-interpretation
#10
Francesca Frau, Daniel Crowther, Hartmut Ruetten, Karla V Allebrandt
Genome-wide association studies (GWAs) for type 2 diabetes (T2D) have been successful in identifying many loci with robust association signals. Nevertheless, there is a clear need for post-GWAs strategies to understand mechanism of action and clinical relevance of these variants. The association of several comorbidities with T2D suggests a common etiology for these phenotypes and complicates the management of the disease. In this study, we focused on the genetics underlying these relationships, using systems genomics to identify genetic variation associated with T2D and 12 other traits...
March 22, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28408159/brain-mrs-glutamine-as-a-biomarker-to-guide-therapy-of-hyperammonemic-coma
#11
Anne H O'Donnell-Luria, Alexander P Lin, Sai K Merugumala, Frances Rohr, Susan E Waisbren, Rebecca Lynch, Vatche Tchekmedyian, Aaron D Goldberg, Andrew Bellinger, J Ricardo McFaline-Figueroa, Tracey Simon, Esteban F Gershanik, Bruce D Levy, David E Cohen, Martin A Samuels, Gerard T Berry, Natasha Y Frank
Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N-carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate...
March 10, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28302345/newborn-screening-for-six-lysosomal-storage-disorders-in-a-cohort-of-mexican-patients-three-year-findings-from-a-screening-program-in-a-closed-mexican-health-system
#12
Juana Inés Navarrete-Martínez, Ana Elena Limón-Rojas, Maria de Jesús Gaytán-García, Jesús Reyna-Figueroa, Guillermo Wakida-Kusunoki, Ma Del Rocío Delgado-Calvillo, Consuelo Cantú-Reyna, Héctor Cruz-Camino, David Eduardo Cervantes-Barragán
OBJECTIVE: To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). STUDY DESIGN: Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease...
March 9, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28285739/neuropsychiatric-comorbidities-in-adults-with-phenylketonuria-a-retrospective-cohort-study
#13
Deborah A Bilder, Joyce A Kobori, Jessica L Cohen-Pfeffer, Erin M Johnson, Elaina R Jurecki, Mitzie L Grant
Adults with phenylketonuria (PKU) may experience neurologic and psychiatric disorders, including intellectual disability, anxiety, depression, and neurocognitive dysfunction. Identifying the prevalence and prevalence ratios of these conditions will inform clinical treatment. This nested, case-controlled study used International Classification of Diseases, Ninth Revision (ICD-9) codes from the MarketScan® insurance claims databases from 2006 to 2012 and healthcare claims data for US-based employer and government-sponsored health plans...
March 6, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28291718/cystathionine-beta-synthase-deficiency-alters-hepatic-phospholipid-and-choline-metabolism-post-translational-repression-of-phosphatidylethanolamine-n-methyltransferase-is-a-consequence-rather-than-a-cause-of-liver-injury-in-homocystinuria
#14
René L Jacobs, Hua Jiang, John P Kennelly, David J Orlicky, Robert H Allen, Sally P Stabler, Kenneth N Maclean
Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC)...
March 2, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28283349/aav-gene-therapy-corrects-otc-deficiency-and-prevents-liver-fibrosis-in-aged-otc-knock-out-heterozygous-mice
#15
Lili Wang, Peter Bell, Hiroki Morizono, Zhenning He, Elena Pumbo, Hongwei Yu, John White, Mark L Batshaw, James M Wilson
Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder of the urea cycle. Hemizygous males and heterozygous females may experience life-threatening elevations of ammonia in blood and brain, leading to irreversible cognitive impairment, coma, and death. Recent evidence of acute liver failure and fibrosis/cirrhosis is also emerging in OTC-deficient patients. Here, we investigated the long-term consequences of abnormal ureagenesis in female mice heterozygous (Het) for a null mutation in the OTC gene...
March 2, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28336152/development-of-hypomelanotic-macules-is-associated-with-constitutive-activated-mtorc1-in-tuberous-sclerosis-complex
#16
Lisbeth Birk Møller, Bitten Schönewolf-Greulich, Thomas Rosengren, Lasse Jonsgaard Larsen, John R Ostergaard, Mette Sommerlund, Caroline Ostenfeldt, Brian Stausbøl-Grøn, Karen Markussen Linnet, Pernille Axél Gregersen, Uffe Birk Jensen
TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1838Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype...
March 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28259708/oral-aversion-to-dietary-sugar-ethanol-and-glycerol-correlates-with-alterations-in-specific-hepatic-metabolites-in-a-mouse-model-of-human-citrin-deficiency
#17
Takeyori Saheki, Kanako Inoue, Hiromi Ono, Yuki Fujimoto, Sumie Furuie, Ken-Ichi Yamamura, Eishi Kuroda, Miharu Ushikai, Akihiro Asakawa, Akio Inui, Kazuhiro Eto, Takashi Kadowaki, Mitsuaki Moriyama, David S Sinasac, Takashi Yamamoto, Tatsuhiko Furukawa, Keiko Kobayashi
Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency...
February 14, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28190699/correcting-false-positive-medium-chain-acyl-coa-dehydrogenase-deficiency-results-from-newborn-screening-synthesis-purification-and-standardization-of-branched-chain-c8-acylcarnitines-for-use-in-their-selective-and-accurate-absolute-quantitation-by-uhplc-ms
#18
Paul E Minkler, Maria S K Stoll, Stephen T Ingalls, Charles L Hoppel
While selectively quantifying acylcarnitines in thousands of patient samples using UHPLC-MS/MS, we have occasionally observed unidentified branched-chain C8 acylcarnitines. Such observations are not possible using tandem MS methods, which generate pseudo-quantitative acylcarnitine "profiles". Since these "profiles" select for mass alone, they cannot distinguish authentic signal from isobaric and isomeric interferences. For example, some of the samples containing branched-chain C8 acylcarnitines were, in fact, expanded newborn screening false positive "profiles" for medium-chain acyl-CoA dehydrogenase deficiency (MCADD)...
February 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28189603/ux007-for-the-treatment-of-long-chain-fatty-acid-oxidation-disorders-safety-and-efficacy-in-children-and-adults-following-24weeks-of-treatment
#19
J Vockley, B Burton, G T Berry, N Longo, J Phillips, A Sanchez-Valle, P Tanpaiboon, S Grunewald, E Murphy, R Humphrey, J Mayhew, A Bowden, L Zhang, J Cataldo, D L Marsden, E Kakkis
BACKGROUND: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid...
February 7, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28216384/novel-homozygous-pck1-mutation-causing-cytosolic-phosphoenolpyruvate-carboxykinase-deficiency-presenting-as-childhood-hypoglycemia-an-abnormal-pattern-of-urine-metabolites-and-liver-dysfunction
#20
Päivi Vieira, Jessie Cameron, Elisa Rahikkala, Riikka Keski-Filppula, Lin-Hua Zhang, Saikat Santra, Allison Matthews, Päivi Myllynen, Matti Nuutinen, Jukka S Moilanen, Richard J Rodenburg, Arndt Rolfs, Johanna Uusimaa, Clara D M van Karnebeek
Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant...
February 6, 2017: Molecular Genetics and Metabolism
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