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Molecular Genetics and Metabolism

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https://www.readbyqxmd.com/read/28645531/new-protein-structures-provide-an-updated-understanding-of-phenylketonuria
#1
REVIEW
Eileen K Jaffe
Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein...
June 15, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28615118/functional-and-biological-studies-of-%C3%AE-galactosidase-a-variants-with-uncertain-significance-from-newborn-screening-in-taiwan
#2
Hsuan-Chieh Liao, Ting-Rong Hsu, Leslie Young, Chuan-Chi Chiang, Chun-Kai Huang, Hao-Chuan Liu, Dau-Ming Niu, Yann-Jang Chen
Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis...
June 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28610913/correlation-between-urinary-gag-and-anti-idursulfase-ert-neutralizing-antibodies-during-treatment-with-nicit-immune-tolerance-regimen-a-case-report
#3
Sarah Kim, Chester B Whitley, Jeanine R Jarnes Utz
INTRODUCTION: Antibodies to intravenous idursulfase enzyme replacement therapy (ERT) for patients with Hunter syndrome (mucopolysaccharidosis type II, MPS II) can have a harmful clinical impact, including both increasing risk of infusion reactions and inhibiting therapeutic activity. Thus, failure to monitor anti-idursulfase antibodies and neutralizing antibodies, and delays in reporting results, may postpone critical clinical decisions. HYPOTHESIS: Urinary glycosaminoglycan (GAG) levels may be used as a biomarker for anti-idursulfase antibodies and neutralizing antibodies to improve timeliness in monitoring and managing ERT...
June 3, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28610912/characteristics-of-cardiomyopathy-in-alstr%C3%A3-m-syndrome-prospective-single-center-data-on-38-patients
#4
Alessandra Brofferio, Vandana Sachdev, Hwaida Hannoush, Jan D Marshall, Jürgen K Naggert, Stanislav Sidenko, Anna Noreuil, Arlene Sirajuddin, Joy Bryant, Joan C Han, Andrew E Arai, William A Gahl, Meral Gunay-Aygun
BACKGROUND: Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely. METHODS: In this single center prospective series of 38 children and adults (age range 1...
May 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28595941/epidemiology-of-mucopolysaccharidoses
#5
Shaukat A Khan, Hira Peracha, Diana Ballhausen, Alfred Wiesbauer, Marianne Rohrbach, Matthias Gautschi, Robert W Mason, Roberto Giugliani, Yasuyuki Suzuki, Kenji E Orii, Tadao Orii, Shunji Tomatsu
The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1...
May 26, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28583327/3-hydroxy-3-methylglutaryl-coenzyme-a-lyase-deficiency-clinical-presentation-and-outcome-in-a-series-of-37-patients
#6
Sarah Catharina Grünert, Sonja Marina Schlatter, Robert Niklas Schmitt, Corinne Gemperle-Britschgi, Lenka Mrázová, Mehmet Cihan Balcı, Felix Bischof, Mahmut Çoker, Anibh M Das, Mübeccel Demirkol, Maaike de Vries, Gülden Gökçay, Johannes Häberle, Sema Kalkan Uçar, Amelie Sophia Lotz-Havla, Thomas Lücke, Dominique Roland, Frank Rutsch, René Santer, Andrea Schlune, Christian Staufner, Karl Otfried Schwab, Grant A Mitchell, Jörn Oliver Sass
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation...
May 22, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28579020/psychosine-a-marker-of-krabbe-phenotype-and-treatment-effect
#7
M L Escolar, B T Kiely, E Shawgo, X Hong, M H Gelb, J J Orsini, D Matern, M D Poe
Newborn screening (NBS) for Krabbe disease, a rare neurodegenerative disorder caused by deficient galactocerebrosidase (GALC) enzyme activity, has recently been implemented in a number of US states. However, the spectrum of phenotypic manifestations associated with deficient GALC activity complicates the management of screen-positive newborns and underscores the need to identify clinically relevant biomarkers. Earlier studies with a small number of patients identified psychosine, a substrate of the GALC enzyme, as a potential biomarker for Krabbe disease...
May 22, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28566233/expanding-the-genetic-cause-of-multiple-sulfatase-deficiency-a-novel-sumf1-variant-in-a-patient-displaying-a-severe-late-infantile-form-of-the-disease
#8
Ilona Jaszczuk, Lars Schlotawa, Thomas Dierks, Andreas Ohlenbusch, Dominique Koppenhöfer, Mariusz Babicz, Monika Lejman, Karthikeyan Radhakrishnan, Agnieszka Ługowska
Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disease caused by defective cellular sulfatases. Activity of sulfatases depends on post-translational modification catalyzed by formylglycine-generating enzyme (FGE), encoded by the SUMF1 gene. SUMF1 pathologic variants cause MSD, a syndrome presenting with a complex phenotype. We describe the first Polish patient with MSD caused by a yet undescribed pathologic variant c.337G>A [p.Glu113Lys] (i.e. p.E113K) in heterozygous combination with the known deletion allele c...
May 22, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28552678/detection-of-6-demethoxyubiquinone-in-coq10-deficiency-disorders-insights-into-enzyme-interactions-and-identification-of-potential-therapeutics
#9
Diran Herebian, Annette Seibt, Sander H J Smits, Gisela Bünning, Christoph Freyer, Holger Prokisch, Daniela Karall, Anna Wredenberg, Anna Wedell, Luis C López, Ertan Mayatepek, Felix Distelmaier
Coenzyme Q10 (CoQ10) is an essential cofactor of the mitochondrial oxidative phosphorylation (OXPHOS) system and its deficiency has important implications for several inherited metabolic disorders of childhood. The biosynthesis of CoQ10 is a complicated process, which involves at least 12 different enzymes. One of the metabolic intermediates that are formed during CoQ10 biosynthesis is the molecule 6-demethoxyubiquinone (6-DMQ). This CoQ precursor is processed at the level of COQ7 and COQ9. We selected this metabolite as a marker substance for metabolic analysis of cell lines with inherited genetic defects (COQ2, COQ4, COQ7 and COQ9) or siRNA knockdown in CoQ biosynthesis enzymes using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)...
May 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28583326/cystathionine-%C3%AE-synthase-deficiency-of-mice-and-men
#10
REVIEW
Warren D Kruger
Cystathionine β-synthase (CBS) deficiency (Online Mendelian Inheritance in Man [OMIM] 236,200) is an autosomal recessive disorder that is caused by mutations in the CBS gene. It is the most common inborn error of sulfur metabolism and is the cause of classical homocystinuria, a condition characterized by very high levels of plasma total homocysteine and methionine. Although recognized as an inborn error of metabolism over 60years ago, these is still much we do not understand related to how this specific metabolic defect gives rise to its distinct phenotypes...
May 19, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28552677/a-long-term-follow-up-study-of-the-development-of-hip-disease-in-mucopolysaccharidosis-type-vi
#11
Esmee Oussoren, Johannes H J M Bessems, Virginie Pollet, Jan C van der Meijden, Lianne J van der Giessen, Iris Plug, Annick S Devos, George J G Ruijter, Ans T van der Ploeg, Mirjam Langeveld
Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology)...
May 19, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28532689/lipid-composition-of-microdomains-is-altered-in-neuronopathic-gaucher-disease-sheep-brain-and-spleen
#12
Leanne K Hein, Tina Rozaklis, Melissa K Adams, John J Hopwood, Litsa Karageorgos
Gaucher disease is a lysosomal storage disorder caused by a deficiency in glucocerebrosidase activity that leads to accumulation of glucosylceramide and glucosylsphingosine. Membrane raft microdomains are discrete, highly organized microdomains with a unique lipid composition that provide the necessary environment for specific protein-lipid and protein-protein interactions to take place. In this study we purified detergent resistant membranes (DRM; membrane rafts) from the occipital cortex and spleen from sheep affected with acute neuronopathic Gaucher disease and wild-type controls...
May 17, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28526293/new-biomarkers-defining-a-novel-early-stage-of-fabry-nephropathy-a-diagnostic-test-study
#13
Patrício Aguiar, Olga Azevedo, Rui Pinto, Jacira Marino, Robert Baker, Carlos Cardoso, José Luís Ducla Soares, Derralynn Hughes
BACKGROUND: Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2...
May 13, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28506702/cognitive-and-adaptive-measurement-endpoints-for-clinical-trials-in-mucopolysaccharidoses-types-i-ii-and-iii-a-review-of-the-literature
#14
REVIEW
Darren Janzen, Kathleen A Delaney, Elsa G Shapiro
Sensitive, reliable measurement instruments are critical for the evaluation of disease progression and new treatments that affect the brain in the mucopolysaccharidoses (MPS). MPS I, II, and III have early onset clinical phenotypes that affect the brain during development and result in devastating cognitive decline and ultimately death without treatment. Comparisons of outcomes are hindered by diverse protocols and approaches to assessment including applicability to international trials necessary in rare diseases...
May 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28566232/identification-and-diagnostic-value-of-phytanoyl-and-pristanoyl-carnitine-in-plasma-from-patients-with-peroxisomal-disorders
#15
Katharina Herzog, Henk van Lenthe, Ronald J A Wanders, Frédéric M Vaz, Hans R Waterham, Sacha Ferdinandusse
Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of peroxisomal disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with α-methylacyl-CoA racemase deficiency. For the diagnosis of peroxisomal disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid...
May 6, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28501294/cognitive-endpoints-for-therapy-development-for-neuronopathic-mucopolysaccharidoses-results-of-a-consensus-procedure
#16
REVIEW
Johanna H van der Lee, Jonathan Morton, Heather R Adams, Lorne Clarke, Berendine Johanne Ebbink, Maria L Escolar, Roberto Giugliani, Paul Harmatz, Melissa Hogan, Simon Jones, Shauna Kearney, Joseph Muenzer, Stewart Rust, Margaret Semrud-Clikeman, Frits A Wijburg, Zi-Fan Yu, Darren Janzen, Elsa Shapiro
The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses...
May 6, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28529009/assembly-defects-of-multiple-respiratory-chain-complexes-in-a-child-with-cardiac-hypertrophy-associated-with-a-novel-acad9-mutation
#17
Konstantina Fragaki, Annabelle Chaussenot, Audrey Boutron, Sylvie Bannwarth, Cecile Rouzier, Brigitte Chabrol, Veronique Paquis-Flucklinger
Patients carrying Acyl-CoA dehydrogenase 9 (ACAD9) mutations reported to date mainly present with severe hypertrophic cardiomyopathy and isolated complex I (CI) dysfunction. Here we report a novel ACAD9 mutation in a young girl presenting with severe hypertrophic cardiomyopathy, isolated CI deficiency and interestingly multiple respiratory chain complexes assembly defects. We show that ACAD9 analysis has to be performed in first intention in patients presenting with cardiac hypertrophy even in the presence of multiple assembly defects...
May 4, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28495078/favourable-effect-of-early-versus-late-start-of-enzyme-replacement-therapy-on-plasma-globotriaosylsphingosine-levels-in-men-with-classical-fabry-disease
#18
Maarten Arends, Frits A Wijburg, Christoph Wanner, Frédéric M Vaz, André B P van Kuilenburg, Derralynn A Hughes, Marieke Biegstraaten, Atul Mehta, Carla E M Hollak, Mirjam Langeveld
BACKGROUND: The level of plasma globotriaosylsphingosine (lysoGb3) is an indication of disease severity in Fabry disease (FD) and its decrease during enzyme replacement therapy could be a reflection of treatment efficacy. Early treatment of FD may improve clinical outcome, but data to support this hypothesis are scarce. In this study we compared lysoGb3 decrease after ERT initiation in men with classical FD who started ERT before the age of 25 (early-treatment) with those who started later in life (late-treatment)...
May 4, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28495044/cognitive-and-academic-outcomes-in-long-term-survivors-of-infantile-onset-pompe-disease-a-longitudinal-follow-up
#19
Gail A Spiridigliozzi, Lori A Keeling, Mihaela Stefanescu, Cindy Li, Stephanie Austin, Priya S Kishnani
This study examines the long-term cognitive and academic outcomes of 11 individuals with infantile onset Pompe disease (IOPD) (median age=11years, 1month, range=5years, 6months through 17years of age) treated with enzyme replacement therapy from an early age. All participants (7 males, 4 females) were administered individual intelligence tests (Wechsler or Leiter scales or both), a measure of their academic skill levels (Woodcock-Johnson Tests of Achievement), and a screening measure of visual-motor integration ability (Beery-Buktenica)...
May 1, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28506393/partial-rescue-of-neuropathology-in-the-murine-model-of-pku-following-administration-of-recombinant-phenylalanine-ammonia-lyase-pegvaliase
#20
Marc Goldfinger, William L Zeile, Carley R Corado, Charles A O'Neill, Laurie S Tsuruda, Philip J Laipis, Jonathan D Cooper
Pegylated recombinant phenylalanine ammonia lyase (pegvaliase) is an enzyme substitution therapy being evaluated for the treatment of phenylketonuria (PKU). PKU is characterized by elevated plasma phenylalanine, which is thought to lead to a deficiency in monoamine neurotransmitters and ultimately, neurocognitive dysfunction. A natural history evaluation in a mouse model of PKU demonstrated a profound decrease in tyrosine hydroxylase (TH) immunoreactivity in several brain regions, beginning at 4weeks of age...
April 29, 2017: Molecular Genetics and Metabolism
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