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Molecular Genetics and Metabolism

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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
#1
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
#2
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
#3
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
#4
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
#5
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/28285122/hypertryptophanemia-due-to-tryptophan-2-3-dioxygenase-deficiency
#6
Patrick Ferreira, Inchul Shin, Iveta Sosova, Kednerlin Dornevil, Shailly Jain, Deborah Dewey, Fange Liu, Aimin Liu
In this report we describe the first human case of hypertryptophanemia confirmed to be due to tryptophan 2,3-dioxygenase deficiency. The underlying etiology was established by sequencing the TDO2 gene, in which there was compound heterozygosity for two rare variants: c.324G>C, p.Met108Ile and c.491dup, p.Ile165Aspfs*12. The pathogenicity of these variants was confirmed by molecular-level studies, which showed that c.491dup does not produce soluble protein and c.324G>C results in a catalytically less efficient Met108Ile enzyme that is prone to proteolytic degradation...
March 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28259707/clinical-and-molecular-phenotyping-of-a-child-with-hermansky-pudlak-syndrome-7-an-uncommon-genetic-type-of-hps
#7
Melanie M Bryan, Nathanial J Tolman, Karen L Simon, Marjan Huizing, Robert B Hufnagel, Brian P Brooks, Vladislav Speransky, James C Mullikin, William A Gahl, May Christine V Malicdan, Bernadette R Gochuico
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. RESULTS: A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising...
February 27, 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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28189602/excess-coenzyme-a-reduces-skeletal-muscle-performance-and-strength-in-mice-overexpressing-human-pank2
#12
Deborah R Corbin, Jerold E Rehg, Danielle L Shepherd, Peter Stoilov, Ryan J Percifield, Linda Horner, Sharon Frase, Yong-Mei Zhang, Charles O Rock, John M Hollander, Suzanne Jackowski, Roberta Leonardi
Coenzyme A (CoA) is a cofactor that is central to energy metabolism and CoA synthesis is controlled by the enzyme pantothenate kinase (PanK). A transgenic mouse strain expressing human PANK2 was derived to determine the physiological impact of PANK overexpression and elevated CoA levels. The Tg(PANK2) mice expressed high levels of the transgene in skeletal muscle and heart; however, CoA was substantially elevated only in skeletal muscle, possibly associated with the comparatively low endogenous levels of acetyl-CoA, a potent feedback inhibitor of PANK2...
February 3, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28202214/lethal-neonatal-case-and-review-of-primary-short-chain-enoyl-coa-hydratase-sceh-deficiency-associated-with-secondary-lymphocyte-pyruvate-dehydrogenase-complex-pdc-deficiency
#13
Jirair K Bedoyan, Samuel P Yang, Sacha Ferdinandusse, Rhona M Jack, Alexander Miron, George Grahame, Suzanne D DeBrosse, Charles L Hoppel, Douglas S Kerr, Ronald J A Wanders
Mutations in ECHS1 result in short-chain enoyl-CoA hydratase (SCEH) deficiency which mainly affects the catabolism of various amino acids, particularly valine. We describe a case compound heterozygous for ECHS1 mutations c.836T>C (novel) and c.8C>A identified by whole exome sequencing of proband and parents. SCEH deficiency was confirmed with very low SCEH activity in fibroblasts and nearly absent immunoreactivity of SCEH. The patient had a severe neonatal course with elevated blood and cerebrospinal fluid lactate and pyruvate concentrations, high plasma alanine and slightly low plasma cystine...
February 2, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28284539/corrigendum-to-next-generation-sequencing-of-patients-with-mut-methylmalonic-aciduria-validation-of-somatic-cell-studies-and-identification-of-16-novel-mutations-mol-genet-metab-aug-2016-118-4-264-71
#14
Jordan Chu, Mihaela Pupavac, David Watkins, Xia Tian, Yanming Feng, Stella Chen, Remington Fenter, Victor W Zhang, Jing Wang, Lee-Jun Wong, David S Rosenblatt
No abstract text is available yet for this article.
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28185884/the-emerging-phenotype-of-late-onset-pompe-disease-a-systematic-literature-review
#15
REVIEW
Justin Chan, Ankit K Desai, Zoheb B Kazi, Kaitlyn Corey, Stephanie Austin, Lisa D Hobson-Webb, Laura E Case, Harrison N Jones, Priya S Kishnani
BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype. PURPOSE: To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006...
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28162992/adherence-to-clinic-recommendations-among-patients-with-phenylketonuria-in-the-united-states
#16
E R Jurecki, S Cederbaum, J Kopesky, K Perry, F Rohr, A Sanchez-Valle, K S Viau, M Y Sheinin, J L Cohen-Pfeffer
OBJECTIVE: Assess current management practices of phenylketonuria (PKU) clinics across the United States (US) based on the key treatment metrics of blood phenylalanine (Phe) concentrations and blood Phe testing frequency, as well as patient adherence to their clinic's management practice recommendations. METHODS: An online survey was conducted with medical professionals from PKU clinics across the US from July to September 2015. Forty-four clinics participated in the survey and account for approximately half of PKU patients currently followed in clinics in the US (Berry et al...
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28122681/phenotypic-and-genotypic-spectrum-of-congenital-disorders-of-glycosylation-type-i-and-type-ii
#17
Amal Al Teneiji, Theodora U J Bruun, Sarah Sidky, Dawn Cordeiro, Ronald D Cohn, Roberto Mendoza-Londono, Mahendranath Moharir, Julian Raiman, Komudi Siriwardena, Lianna Kyriakopoulou, Saadet Mercimek-Mahmutoglu
BACKGROUND: Congenital disorders of glycosylation (CDG) are inborn defects of glycan metabolism. They are multisystem disorders. Analysis of transferrin isoforms is applied as a screening test for CDG type I (CDG-I) and type II (CDG-II). We performed a retrospective cohort study to determine spectrum of phenotype and genotype and prevalence of the different subtypes of CDG-I and CDG-II. MATERIAL AND METHODS: All patients with CDG-I and CDG-II evaluated in our institution's Metabolic Genetics Clinics were included...
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28096054/glycogen-storage-disease-type-ia-mice-with-less-than-2-of-normal-hepatic-glucose-6-phosphatase-%C3%AE-activity-restored-are-at-risk-of-developing-hepatic-tumors
#18
Goo-Young Kim, Young Mok Lee, Joon Hyun Kwon, Jun-Ho Cho, Chi-Jiunn Pan, Matthew F Starost, Brian C Mansfield, Janice Y Chou
Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6pc-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3-63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown...
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28089346/detection-of-unusual-very-long-chain-fatty-acid-and-ether-lipid-derivatives-in-the-fibroblasts-and-plasma-of-patients-with-peroxisomal-diseases-using-liquid-chromatography-mass-spectrometry
#19
Shigeo Takashima, Kayoko Toyoshi, Takahiro Itoh, Naomi Kajiwara, Ayako Honda, Akiko Ohba, Shoko Takemoto, Satoshi Yoshida, Nobuyuki Shimozawa
Metabolic changes occur in patients with peroxisomal diseases owing to impairments in the genes involved in peroxisome function. For diagnostic purposes, saturated very-long-chain fatty acids (VLCFAs) such as C24:0 and C26:0, phytanic acid, pristanic acid, and plasmalogens are often measured as metabolic hallmarks. As the direct pathology of peroxisomal disease is yet to be fully elucidated, we sought to explore the fatty acid species that accumulate in patients with peroxisomal diseases. We developed a method for detecting a range of fatty acids implicated in peroxisomal diseases such as Zellweger syndrome (ZS) and X-linked adrenoleukodystrophy (X-ALD)...
March 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28087245/the-severe-clinical-phenotype-for-a-heterozygous-fabry-female-patient-correlates-to-the-methylation-of-non-mutated-allele-associated-with-chromosome-10q26-deletion-syndrome
#20
Mohammad Arif Hossain, Hiroko Yanagisawa, Takashi Miyajima, Chen Wu, Ayumi Takamura, Keiko Akiyama, Rina Itagaki, Kaoru Eto, Takeo Iwamoto, Takayuki Yokoi, Kenji Kurosawa, Hironao Numabe, Yoshikatsu Eto
Heterozygous Fabry females usually have an attenuated form of Fabry disease, causing them to be symptomatic; however, in rare cases, they can present with a severe phenotype. In this study, we report on a 37-year-old woman with acroparesthesia, a dysmorphic face, left ventricular hypertrophy, and intellectual disability. Her father had Fabry disease and died due to chronic renal and congestive cardiac failure. Her paternal uncle had chronic renal failure and intellectual disability, and her paternal aunt was affected with congestive cardiac failure...
March 2017: Molecular Genetics and Metabolism
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