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Molecular Genetics and Metabolism

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https://www.readbyqxmd.com/read/28739202/the-relationship-between-dietary-intake-growth-and-body-composition-in-phenylketonuria
#1
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
#2
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
https://www.readbyqxmd.com/read/28712602/anaplerotic-therapy-in-propionic-acidemia
#3
Nicola Longo, Leisa B Price, Eduard Gappmaier, Nancy L Cantor, Sharon L Ernst, Carrie Bailey, Marzia Pasquali
BACKGROUND: Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. PURPOSE: The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7...
July 12, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28711407/severe-neuroimaging-anomalies-are-usually-associated-with-random-x-inactivation-in-leucocytes-circulating-dna-in-x-linked-dominant-incontinentia-pigmenti
#4
Volodia Dangouloff-Ros, Smail Hadj-Rabia, Judite Oliveira Santos, Elodie Bal, Isabelle Desguerre, Manoelle Kossorotoff, Isabelle An, Asma Smahi, Christine Bodemer, Arnold Munnich, Julie Steffann, Nathalie Boddaert
Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes circulating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI (n=5), mild white matter abnormalities with cortical and corpus callosum atrophy (n=6), and severe cortical abnormalities suggesting a vascular disease (n=7)...
July 10, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28711408/biochemical-characteristics-of-newborns-with-carnitine-transporter-defect-identified-by-newborn-screening-in-california
#5
N M Gallant, K Leydiker, Y Wilnai, C Lee, F Lorey, L Feuchtbaum, H Tang, J Carter, G M Enns, S Packman, H J Lin, W R Wilcox, S D Cederbaum, J E Abdenur
Carnitine transporter defect (CTD; also known as systemic primary carnitine deficiency; MIM 212140) is due to mutations in the SLC22A5 gene and leads to extremely low carnitine levels in blood and tissues. Affected individuals may develop early onset cardiomyopathy, weakness, or encephalopathy, which may be serious or even fatal. The disorder can be suggested by newborn screening. However, markedly low newborn carnitine levels can also be caused by conditions unrelated to CTD, such as the low carnitine levels often associated with normal pregnancies and some metabolic disorders occurring in the mother...
July 8, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28728877/genotype-phenotype-and-disease-severity-reflected-by-serum-lysogb3-levels-in-patients-with-fabry-disease
#6
Albina Nowak, Thomas P Mechtler, Thorsten Hornemann, Joanna Gawinecka, Eva Theswet, Max J Hilz, David C Kasper
BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene causing deficiency of α-galactosidase A which results in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3), in body liquids and lysosomes. In a large cohort of FD patients, we aimed to establish genotype/phenotype relations as indicated by serum LysoGb3 (deacylated Gb3). METHODS: In 69 consecutive adult FD patients (males: n=28 (41%)) with a GLA-mutation confirmed diagnosis, we conducted a multidisciplinary clinical characterization during their routine annual examinations, and measured serum LysoGb3 levels by high-sensitive electrospray ionization liquid chromatography tandem mass spectrometry...
July 5, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28688840/impact-of-clinical-exomes-in-neurodevelopmental-and-neurometabolic-disorders
#7
Christina Evers, Christian Staufner, Martin Granzow, Nagarajan Paramasivam, Katrin Hinderhofer, Lilian Kaufmann, Christine Fischer, Christian Thiel, Thomas Opladen, Urania Kotzaeridou, Stefan Wiemann, Matthias Schlesner, Roland Eils, Stefan Kölker, Claus R Bartram, Georg F Hoffmann, Ute Moog
Whole exome sequencing (WES) is well established in research and is now being introduced into clinically indicated diagnostics (so-called clinical exomes). We evaluated the diagnostic yield and clinical implications of WES in 72 patients from 60 families with undiagnosed neurodevelopmental disorders (NDD), neurometabolic disorders, and dystonias. Pathogenic or likely pathogenic variants leading to a molecular diagnosis could be identified in 21 of the 60 families (overall 35%, in 36% of patients with NDD, in 43% of patients with neurometabolic disorders, in 25% of patients with dystonias)...
June 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28693988/milder-clinical-and-biochemical-phenotypes-associated-with-the-c-482g-a-p-arg161gln-pathogenic-variant-in-cobalamin-c-disease-implications-for-management-and-screening
#8
Mohammed Almannai, Ronit Marom, Kristian Divin, Fernando Scaglia, V Reid Sutton, William J Craigen, Brendan Lee, Lindsay C Burrage, Brett H Graham
INTRODUCTION: Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c...
June 29, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28689740/clinical-presentation-and-outcome-in-a-series-of-32-patients-with-2-methylacetoacetyl-coenzyme-a-thiolase-mat-deficiency
#9
Sarah Catharina Grünert, Robert Niklas Schmitt, Sonja Marina Schlatter, Corinne Gemperle-Britschgi, Mehmet Cihan Balcı, Volker Berg, Mahmut Çoker, Anibh M Das, Mübeccel Demirkol, Terry G J Derks, Gülden Gökçay, Sema Kalkan Uçar, Vassiliki Konstantopoulou, G Christoph Korenke, Amelie Sophia Lotz-Havla, Andrea Schlune, Christian Staufner, Christel Tran, Gepke Visser, Karl Otfried Schwab, Toshiyuki Fukao, Jörn Oliver Sass
2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union...
June 27, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28673550/a-rare-case-of-sterol-c4-methyl-oxidase-deficiency-in-a-young-italian-male-biochemical-and-molecular-characterization
#10
Giulia Frisso, Monica Gelzo, Elena Procopio, Concetta Sica, Maria Pia Lenza, Antonio Dello Russo, Maria Alice Donati, Francesco Salvatore, Gaetano Corso
Inborn defects of cholesterol biosynthesis are metabolic disorders presenting with multi-organ and tissue anomalies. An autosomal recessive defect involving the demethylating enzyme C4-methyl sterol (SC4MOL) has been reported in only 4 patients so far. In infancy, all patients were affected by microcephaly, bilateral congenital cataracts, growth delay, psoriasiform dermatitis, immune dysfunction, and intellectual disability. Herein, we describe a new case of SC4MOL deficiency in which a 19-year-old Italian male was affected by bilateral congenital cataracts, growth delay and learning disabilities, behavioral disorders and small stature, but not microcephaly...
June 27, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28673551/analyses-of-slc13a5-epilepsy-patients-reveal-perturbations-of-tca-cycle
#11
Matthew N Bainbridge, Erin Cooney, Marcus Miller, Adam D Kennedy, Jacob E Wulff, Taraka Donti, Shalini N Jhangiani, Richard A Gibbs, Sarah H Elsea, Brenda E Porter, Brett H Graham
OBJECTIVE: To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. METHODS: Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. RESULTS: Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain...
June 24, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28666653/the-liver-is-a-metabolic-and-immunologic-organ-a-reconsideration-of-metabolic-decompensation-due-to-infection-in-inborn-errors-of-metabolism-iem
#12
REVIEW
Tatyana N Tarasenko, Peter J McGuire
Metabolic decompensation in inborn errors of metabolism (IEM) is characterized by a rapid deterioration in metabolic status leading to life-threatening biochemical perturbations (e.g. hypoglycemia, hyperammonemia, acidosis, organ failure). Infection is the major cause of metabolic decompensation in patients with IEM. We hypothesized that activation of the immune system during infection leads to further perturbations in end-organ metabolism resulting in increased morbidity. To address this, we established model systems of metabolic decompensation due to infection...
June 24, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28659245/newborn-screening-for-hyperargininemia-due-to-arginase-1-deficiency
#13
Bradford L Therrell, Robert Currier, David Lapidus, Meredith Grimm, Stephen D Cederbaum
Hyperargininemia caused by Arginase 1 deficiency is a rare disorder of the urea cycle that can be diagnosed by elevation of arginine in newborn screening blood spots when analyzed by tandem mass spectrometry. Hyperargininemia is currently included as a secondary target on the U.S. Recommended Uniform Screening Panel, which directly influences state-based newborn screening. Because of the apparent low disease frequency and lack of case detection and treatment data, detailed attention has not been given to a model newborn screening algorithm including appropriate analytical cutoff values for disease indicators...
June 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28648663/effect-of-enzyme-replacement-therapy-with-alglucosidase-alfa-myozyme%C3%A2-in-12-patients-with-advanced-late-onset-pompe-disease
#14
Constantinos Papadopoulos, David Orlikowski, Hélène Prigent, Arnaud Lacour, Céline Tard, Alain Furby, Julien Praline, Guilhem Solé, Jean-Yves Hogrel, Marie De Antonio, Claudio Semplicini, Joelle Deibener-Kaminsky, Pierre Kaminsky, Bruno Eymard, Nadjib Taouagh, Barbara Perniconi, Dalil Hamroun, Pascal Laforêt
BACKGROUND: The efficacy of enzyme replacement therapy (ERT) in patients at an advanced stage of Pompe disease has only been addressed in a few studies. Our objective was to assess the long term effects of ERT in a cohort of patients with severe Pompe disease. METHODS: We identified patients from the French Pompe Registry with severe respiratory failure and permanent wheelchair use (assisted walk for a few meters was allowed) when starting ERT. Patients' medical records were collected and reviewed and respiratory and motor functions, before ERT initiation and upon last evaluation were compared...
June 20, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28673549/biochemical-and-genetic-characterization-of-an-unusual-mild-pex3-related-zellweger-spectrum-disorder
#15
Kathrine Bjørgo, Roar Fjær, Hanne Håberg Mørk, Sacha Ferdinandusse, Kim D Falkenberg, Hans R Waterham, Ane-Marte Øye, Alma Sikiric, Silja Svanstrøm Amundsen, Mari Ann Kulseth, Kaja Selmer
Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype...
June 17, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28663131/correlation-of-lyso-gb3-levels-in-dried-blood-spots-and-sera-from-patients-with-classic-and-later-onset-fabry-disease
#16
Albina Nowak, Thomas Mechtler, David C Kasper, Robert J Desnick
BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A) and the accumulation of its substrates, globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Here, we compared the levels of Lyso-Gb3 in dried blood spots (DBS) and sera in affected males and heterozygotes with the "Classic" and "Later-Onset" phenotypes. METHODS: The Lyso-Gb3 concentrations in DBS and sera from 56 FD patients were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry...
June 17, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28645531/new-protein-structures-provide-an-updated-understanding-of-phenylketonuria
#17
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
#18
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
#19
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/28684086/modifier-genes-moving-from-pathogenesis-to-therapy
#20
Edward R B McCabe
This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms...
May 30, 2017: Molecular Genetics and Metabolism
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