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Molecular Genetics and Metabolism

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https://www.readbyqxmd.com/read/28918066/enzymatic-testing-sensitivity-variability-and-practical-diagnostic-algorithm-for-pyruvate-dehydrogenase-complex-pdc-deficiency
#1
Ha Kyung Shin, George Grahame, Shawn E McCandless, Douglas S Kerr, Jirair K Bedoyan
Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia in children. Prompt and correct diagnosis of PDC deficiency and differentiating between specific vs generalized, or secondary deficiencies has important implications for clinical management and therapeutic interventions. Both genetic and enzymatic testing approaches are being used in the diagnosis of PDC deficiency. However, the diagnostic efficacy of such testing approaches for individuals affected with PDC deficiency has not been systematically investigated in this disorder...
September 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28916119/safety-and-efficacy-of-glycerol-phenylbutyrate-for-management-of-urea-cycle-disorders-in-patients-aged-2months-to-2years
#2
Susan A Berry, Nicola Longo, George A Diaz, Shawn E McCandless, Wendy E Smith, Cary O Harding, Roberto Zori, Can Ficicioglu, Uta Lichter-Konecki, Beth Robinson, Jerry Vockley
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US for the management of patients 2months of age and older with urea cycle disorders (UCDs) that cannot be managed with protein restriction and/or amino acid supplementation alone. Limited data exist on the use of nitrogen conjugation agents in very young patients. METHODS: Seventeen patients (15 previously on other nitrogen scavengers) with all types of UCDs aged 2months to 2years were switched to, or started, GPB...
September 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28919002/x-linked-adrenoleukodystrophy-in-a-chimpanzee-due-to-an-abcd1-mutation-reported-in-multiple-unrelated-humans
#3
Julian Curiel, Steven Jeffrey Steinberg, Sarah Bright, Ann Snowden, Ann B Moser, Florian Eichler, Holly A Dubbs, Joseph G Hacia, John J Ely, Jocelyn Bezner, Alisa Gean, Adeline Vanderver
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder leading to the accumulation of very long chain fatty acids (VLCFA) due to a mutation in the ABCD1 gene. ABCD1 mutations lead to a variety of phenotypes, including cerebral X-ALD and adrenomyeloneuropathy (AMN) in affected males and 80% of carrier females. There is no definite genotype-phenotype correlation with intrafamilial variability. Cerebral X-ALD typically presents in childhood, but can also present in juveniles and adults...
September 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28888852/renal-endoplasmic-reticulum-stress-is-coupled-to-impaired-autophagy-in-a-mouse-model-of-gsd-ia
#4
Benjamin L Farah, Dustin J Landau, Yajun Wu, Rohit A Sinha, Alwin Loh, Boon-Huat Bay, Dwight D Koeberl, Paul M Yen
GSD Ia (von Gierke Disease, Glycogen Storage Disease Type Ia) is a devastating genetic disorder with long-term sequelae, such as non-alcoholic fatty liver disease and renal failure. Down-regulated autophagy is involved in the development of hepatic metabolic dysfunction in GSD Ia; however, the role of autophagy in the renal pathology is unknown. Here we show that autophagy is impaired and endoplasmic reticulum (ER) stress is increased in the kidneys of a mouse model of GSD Ia. Induction of autophagy by rapamycin also reduces this ER stress...
September 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28888854/quantitation-of-phenylbutyrate-metabolites-by-uplc-ms-ms-demonstrates-inverse-correlation-of-phenylacetate-phenylacetylglutamine-ratio-with-plasma-glutamine-levels
#5
Yi Jiang, Mohammed Almannai, V Reid Sutton, Qin Sun, Sarah H Elsea
Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels...
August 31, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28888851/long-term-longitudinal-study-of-muscle-function-in-patients-with-glycogen-storage-disease-type-iiia
#6
Valérie Decostre, Pascal Laforêt, Marie De Antonio, Kahina Kachetel, Aurélie Canal, Gwenn Ollivier, Aleksandra Nadaj-Pakleza, François M Petit, Karim Wahbi, Abdallah Fayssoil, Bruno Eymard, Anthony Behin, Philippe Labrune, Jean-Yves Hogrel
Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required...
August 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28882528/impaired-glycogen-breakdown-and-synthesis-in-phosphoglucomutase-1-deficiency
#7
Nicolai Preisler, Jonathan Cohen, Christoffer Rasmus Vissing, Karen Lindhardt Madsen, Katja Heinicke, Lydia Jane Sharp, Lauren Phillips, Nadine Romain, Sun Young Park, Marta Newby, Phil Wyrick, Pedro Mancias, Henrik Galbo, John Vissing, Ronald Gerald Haller
OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis. METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response...
August 25, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28851512/reductions-in-glucosylsphingosine-lyso-gb1-in-treatment-na%C3%A3-ve-and-previously-treated-patients-receiving-velaglucerase-alfa-for-type-1-gaucher-disease-data-from-phase-3-clinical-trials
#8
Deborah Elstein, Björn Mellgard, Quinn Dinh, Lan Lan, Yongchang Qiu, Claudia Cozma, Sabrina Eichler, Tobias Böttcher, Ari Zimran
Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (β-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD...
August 24, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28863857/revised-consensus-statement-on-the-preventive-and-symptomatic-care-of-patients-with-leukodystrophies
#9
REVIEW
Laura A Adang, Omar Sherbini, Laura Ball, Miriam Bloom, Anil Darbari, Hernan Amartino, Donna DiVito, Florian Eichler, Maria Escolar, Sarah H Evans, Ali Fatemi, Jamie Fraser, Leslie Hollowell, Nicole Jaffe, Christopher Joseph, Mary Karpinski, Stephanie Keller, Ryan Maddock, Edna Mancilla, Bruce McClary, Jana Mertz, Kiley Morgart, Thomas Langan, Richard Leventer, Sumit Parikh, Amy Pizzino, Erin Prange, Deborah L Renaud, William Rizzo, Jay Shapiro, Dean Suhr, Teryn Suhr, Davide Tonduti, Jacque Waggoner, Amy Waldman, Nicole I Wolf, Ayelet Zerem, Joshua L Bonkowsky, Genevieve Bernard, Keith van Haren, Adeline Vanderver
Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies...
August 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28847675/a-simple-method-for-quantification-of-plasma-globotriaosylsphingosine-utility-for-fabry-disease
#10
Andrew Talbot, Kathy Nicholls, Janice M Fletcher, Maria Fuller
Fabry disease (FD) results from impaired globotriaosylceramide (Gb3) catabolism, due to a deficiency of the lysosomal hydrolase, α-galactosidase A (α-GalA). As a direct consequence, the deacetylated derivative, globotriaosylsphingosine (lyso-Gb3), is produced and contemporary evidence exemplifies its use as a biomarker. Here we developed a simple method to enable quantification of lyso-Gb3 in just 0.01mL of plasma and explored its concentration in a cohort of 73 Australian FD patients, as well as in individuals with other sphingolipidoses...
August 19, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28818555/pyridoxine-5-phosphate-oxidase-pnpo-deficiency-clinical-and-biochemical-alterations-associated-with-the-c-347g-a-p-%C3%A2-arg116gln-mutation
#11
Martino L di Salvo, Mario Mastrangelo, Isabel Nogués, Manuela Tolve, Alessandro Paiardini, Carla Carducci, Davide Mei, Martino Montomoli, Angela Tramonti, Renzo Guerrini, Roberto Contestabile, Vincenzo Leuzzi
BACKGROUND: Pyridoxal-5(')-phosphate oxidase (PNPO) deficiency presents as a severe neonatal encephalopathy responsive to pyridoxal-5(')-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected genetic variants on PNPO gene whose pathogenic role and clinical expression remain to be established. OBJECTIVE: This paper aims to characterize the functional effects of the c.347G>A (p.Arg116Gln) mutation in the PNPO gene in order to define its pathogenicity and describe the clinical features of new patients with epilepsy carrying this mutation...
August 12, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28847676/exploring-the-patient-journey-to-diagnosis-of-gaucher-disease-from-the-perspective-of-212-patients-with-gaucher-disease-and-16-gaucher-expert-physicians
#12
Atul Mehta, Nadia Belmatoug, Bruno Bembi, Patrick Deegan, Deborah Elstein, Özlem Göker-Alpan, Elena Lukina, Eugen Mengel, Kimitoshi Nakamura, Gregory M Pastores, Jordi Pérez López, Ida Schwartz, Christine Serratrice, Jeffrey Szer, Ari Zimran, Maja Di Rocco, Zoya Panahloo, David J Kuter, Derralynn Hughes
Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor...
August 4, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28803783/impact-of-mutations-within-the-fe-s-cluster-or-the-lipoic-acid-biosynthesis-pathways-on-mitochondrial-protein-expression-profiles-in-fibroblasts-from-patients
#13
E Lebigot, P Gaignard, I Dorboz, A Slama, M Rio, P de Lonlay, B Héron, F Sabourdy, O Boespflug-Tanguy, A Cardoso, F Habarou, C Ottolenghi, P Thérond, C Bouton, M P Golinelli-Cohen, A Boutron
Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron‑sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery...
August 3, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28918065/the-role-of-epigenetics-in-lysosomal-storage-disorders-uncharted-territory
#14
REVIEW
Shahzeb Hassan, Ellen Sidransky, Nahid Tayebi
The study of the contribution of epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, to human disease has enhanced our understanding of different cellular processes and diseased states, as well as the effect of environmental factors on phenotypic outcomes. Epigenetic studies may be particularly relevant in evaluating the clinical heterogeneity observed in monogenic disorders. The lysosomal storage disorders are Mendelian disorders characterized by a wide spectrum of associated phenotypes, ranging from neonatal presentations to symptoms that develop in late adulthood...
August 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28801073/newborn-screening-for-carnitine-palmitoyltransferase-ii-deficiency-using-c16-c18-1-c2-evaluation-of-additional-indices-for-adequate-sensitivity-and-lower-false-positivity
#15
Go Tajima, Keiichi Hara, Miyuki Tsumura, Reiko Kagawa, Satoshi Okada, Nobuo Sakura, Shinsuke Maruyama, Atsuko Noguchi, Tomonari Awaya, Mika Ishige, Nobuyuki Ishige, Ikuma Musha, Sayaka Ajihara, Akira Ohtake, Etsuo Naito, Yusuke Hamada, Tomotaka Kono, Tomoko Asada, Hideo Sasai, Toshiyuki Fukao, Ryoji Fujiki, Osamu Ohara, Ryosuke Bo, Kenji Yamada, Hironori Kobayashi, Yuki Hasegawa, Seiji Yamaguchi, Masaki Takayanagi, Ikue Hata, Yosuke Shigematsu, Masao Kobayashi
BACKGROUND: Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available. METHODS: We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices...
July 31, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28888853/monitoring-guidance-for-patients-with-hypophosphatasia-treated-with-asfotase-alfa
#16
REVIEW
Priya S Kishnani, Eric T Rush, Paul Arundel, Nick Bishop, Kathryn Dahir, William Fraser, Paul Harmatz, Agnès Linglart, Craig F Munns, Mark E Nunes, Howard M Saal, Lothar Seefried, Keiichi Ozono
Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures...
July 25, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28774709/treatment-with-antioxidants-ameliorates-oxidative-damage-in-a-mouse-model-of-propionic-acidemia
#17
Ana Rivera-Barahona, Esmeralda Alonso-Barroso, Belén Pérez, Michael P Murphy, Eva Richard, Lourdes R Desviat
Oxidative stress contributes to the pathogenesis of propionic acidemia (PA), a life threatening disease caused by the deficiency of propionyl CoA-carboxylase, in the catabolic pathway of branched-chain amino acids, odd-number chain fatty acids and cholesterol. Patients develop multisystemic complications including seizures, extrapyramidal symptoms, basal ganglia deterioration, pancreatitis and cardiomyopathy. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species and oxidative damage, all of which have been documented in patients' samples and in a hypomorphic mouse model...
July 25, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28757239/beyond-mrna-the-role-of-non-coding-rnas-in-normal-and-aberrant-hematopoiesis
#18
REVIEW
Mark C Wilkes, Claire E Repellin, Kathleen M Sakamoto
The role of non-coding Ribonucleic Acids (ncRNAs) in biology is currently an area of intense focus. Hematopoiesis requires rapidly changing regulatory molecules to guide appropriate differentiation and ncRNA are well suited for this. It is not surprising that virtually all aspects of hematopoiesis have roles for ncRNAs assigned to them and doubtlessly much more await characterization. Stem cell maintenance, lymphoid, myeloid and erythroid differentiation are all regulated by various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and various transposable elements within the genome...
July 25, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28739202/the-relationship-between-dietary-intake-growth-and-body-composition-in-phenylketonuria
#19
Maureen Evans, Helen Truby, Avihu Boneh
AIM: Phenylketonuria (PKU) is an inborn error of protein metabolism that results from perturbation in phenylalanine hydroxylase activity leading to elevated blood levels of phenylalanine (phe). We aimed to explore the relationships between dietary patterns (total-protein, natural-protein, amino-acid formula), and the ratio of protein to energy intake with growth and body composition. METHOD: Longitudinal prospective data (1-6 measurements) of growth, dietary intake and body composition in patients treated with phe-restricted diet only (D-PKU; n=32), and tetrahydrobiopterin (BH4)±phe-restricted diet (BH4-PKU; n=5) were collected over a two-year period...
July 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28739201/neonatal-detection-of-aicardi-gouti%C3%A3-res-syndrome-by-increased-c26-0-lysophosphatidylcholine-and-interferon-signature-on-newborn-screening-blood-spots
#20
Thais Armangue, Joseph J Orsini, Asako Takanohashi, Francesco Gavazzi, Alex Conant, Nicole Ulrick, Mark A Morrissey, Norah Nahhas, Guy Helman, Heather Gordish-Dressman, Simona Orcesi, Davide Tonduti, Chloe Stutterd, Keith van Haren, Camilo Toro, Alejandro D Iglesias, Marjo S van der Knaap, Raphaela Goldbach Mansky, Anne B Moser, Richard O Jones, Adeline Vanderver
BACKGROUND: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS...
July 20, 2017: Molecular Genetics and Metabolism
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