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Molecular Genetics and Metabolism

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https://www.readbyqxmd.com/read/29779903/glycosaminoglycans-analysis-in-blood-and-urine-of-patients-with-mucopolysaccharidosis
#1
Shaukat A Khan, Robert W Mason, Roberto Giugliani, Kenji Orii, Toshiyuki Fukao, Yasuyuki Suzuki, Seiji Yamaguchi, Hironori Kobayashi, Tadao Orii, Shunji Tomatsu
To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls...
May 17, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29779902/molecular-genetics-and-metabolism-special-edition-diagnosis-diagnosis-and-prognosis-of-mucopolysaccharidosis-iva
#2
REVIEW
Hira Peracha, Kazuki Sawamoto, Lauren Averill, Heidi Kecskemethy, Mary Theroux, Mihir Thacker, Kyoko Nagao, Christian Pizarro, William Mackenzie, Hironori Kobayashi, Seiji Yamaguchi, Yasuyuki Suzuki, Kenji Orii, Tadao Orii, Toshiyuki Fukao, Shunji Tomatsu
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is an autosomal recessive disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to the accumulation of specific glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are mainly synthesized in the cartilage. Therefore, the substrates are stored primarily in the cartilage and its extracellular matrix (ECM), leading to a direct impact on bone development and successive systemic skeletal spondylepiphyseal dysplasia...
May 15, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29759592/ccdc115-cdg-a-new-rare-and-misleading-inherited-cause-of-liver-disease
#3
Muriel Girard, Aurélia Poujois, Monique Fabre, Florence Lacaille, Dominique Debray, Marlène Rio, François Fenaille, Sophie Cholet, Coralie Ruel, Elizabeth Caussé, Janick Selves, Laure Bridoux-Henno, France Woimant, Thierry Dupré, Sandrine Vuillaumier-Barrot, Nathalie Seta, Laurent Alric, Pascale de Lonlay, Arnaud Bruneel
Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement...
May 9, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29789193/deoxysphingolipid-precursors-indicate-abnormal-sphingolipid-metabolism-in-individuals-with-primary-and-secondary-disturbances-of-serine-availability
#4
C R Ferreira, S M I Goorden, A Soldatos, H M Byers, J M M Ghauharali-van der Vlugt, F S Beers-Stet, C Groden, C D van Karnebeek, W A Gahl, F M Vaz, X Jiang, H J Vernon
Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length...
May 7, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29747998/delayed-development-of-ossification-centers-in-the-tibia-of-prenatal-and-early-postnatal-mps-vii-mice
#5
Zhirui Jiang, Ainslie L K Derrick-Roberts, Matilda R Jackson, Charné Rossouw, Carmen E Pyragius, Cory Xian, Janice Fletcher, Sharon Byers
Short stature is a characteristic feature of most of the mucopolysaccharidoses, a group of inherited lysosomal storage disorders caused by a single enzyme deficiency. MPS patients present with progressive skeletal defects from an early age, including short stature due to impaired cartilage-to-bone conversion (endochondral ossification). The aim of this study was to determine which murine MPS model best reproduces the bone length reduction phenotype of human MPS and use this model to determine the earliest developmental stage when disrupted endochondral ossification first appears...
May 3, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29735374/clinical-and-molecular-spectrum-of-thymidine-kinase-2-related-mtdna-maintenance-defect
#6
Julia Wang, Emily Kim, Honzheng Dai, Vikki Stefans, Hannes Vogel, Fatma Al Jasmi, Samantha A Schrier Vergano, Diana Castro, Saunder Bernes, Vikas Bhambhani, Catherine Long, Ayman W El-Hattab, Lee-Jun Wong
Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants...
April 28, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29735373/natural-history-of-echocardiographic-abnormalities-in-mucopolysaccharidosis-iii
#7
Carolyn M Wilhelm, Kristen V Truxal, Kim L McBride, John P Kovalchin, Kevin M Flanigan
BACKGROUND: Mucopolysaccharidosis (MPS) type III, Sanfilippo Syndrome, is an autosomal recessive lysosomal storage disorder. MPS I and II patients often develop cardiac involvement leading to early mortality, however there are limited data in MPS III. The objective of this study is to describe cardiac abnormalities in a large group of MPS III patients followed in a longitudinal natural history study designed to determine outcome measures for gene transfer trials. METHODS: A single center study of MPS III patients who were enrolled in the Nationwide Children's Hospital natural history study in 2014...
April 27, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29785937/the-effect-of-enzyme-replacement-therapy-on-clinical-outcomes-in-paediatric-patients-with-fabry-disease-a-systematic-literature-review-by-a-european-panel-of-experts
#8
REVIEW
Marco Spada, Ralf Baron, Perry M Elliott, Bruno Falissard, Max J Hilz, Lorenzo Monserrat, Camilla Tøndel, Anna Tylki-Szymańska, Christoph Wanner, Dominique P Germain
BACKGROUND: Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease...
April 26, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29747997/the-beneficial-effects-of-long-term-enzyme-replacement-therapy-on-cardiac-involvement-in-japanese-fabry-patients
#9
Kenichi Hongo, Keiichi Ito, Taro Date, Ikuko Anan, Yasunori Inoue, Satoshi Morimoto, Kazuo Ogawa, Makoto Kawai, Hiroshi Kobayashi, Masahisa Kobayashi, Hiroyuki Ida, Toya Ohashi, Ikuo Taniguchi, Michihiro Yoshimura, Yoshikatsu Eto
Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years)...
April 26, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29724658/human-hepatocyte-transplantation-corrects-the-inherited-metabolic-liver-disorder-arginase-deficiency-in-mice
#10
Stephanie A K Angarita, Brian Truong, Suhail Khoja, Matthew Nitzahn, Abha K Rajbhandari, Irina Zhuravka, Sergio Duarte, Michael G Lin, Alex K Lam, Stephen D Cederbaum, Gerald S Lipshutz
The transplantation, engraftment, and expansion of primary hepatocytes have the potential to be an effective therapy for metabolic disorders of the liver including those of nitrogen metabolism. To date, such methods for the treatment of urea cycle disorders in murine models has only been minimally explored. Arginase deficiency, an inherited disorder of nitrogen metabolism that presents in the first two years of life, has the potential to be treated by such methods. To explore the potential of this approach, we mated the conditional arginase deficient mouse with a mouse model deficient in fumarylacetoacetate hydrolase (FAH) and with Rag2 and IL2-Rγ mutations to give a selective advantage to transplanted (normal) human hepatocytes...
April 21, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29703588/newborn-screening-for-proximal-urea-cycle-disorders-current-evidence-supporting-recommendations-for-newborn-screening
#11
J Lawrence Merritt, Linnea L Brody, Gisele Pino, Piero Rinaldo
Current newborn screening (NBS) for urea cycle disorders (UCD) is incomplete as only distal UCDs are included in most NBS programs by measuring elevated amino acid concentrations. NBS for the proximal UCDs involves the detection in NBS spots of low citrulline values, a finding which is often overlooked because it is considered to be inadequate. We retrospectively analyzed NBS blood spots from known UCD patients comparing the utility of the Region 4 Stork (R4S) interpretive tools to conventional cutoff based interpretation...
April 20, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29716835/enzyme-replacement-therapy-with-velmanase-alfa-human-recombinant-alpha-mannosidase-novel-global-treatment-response-model-and-outcomes-in-patients-with-alpha-mannosidosis
#12
Paul Harmatz, Federica Cattaneo, Diego Ardigò, Silvia Geraci, Julia B Hennermann, Nathalie Guffon, Allan Lund, Christian J Hendriksz, Line Borgwardt
Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of patients with non-neurological manifestations of mild to moderate alpha-mannosidosis...
April 18, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29724657/therapeutic-goals-in-fabry-disease-recommendations-of-a-european-expert-panel-based-on-current-clinical-evidence-with-enzyme-replacement-therapy
#13
Christoph Wanner, Dominique P Germain, Max J Hilz, Marco Spada, Bruno Falissard, Perry M Elliott
No abstract text is available yet for this article.
April 11, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29661557/a-new-therapy-prevents-intellectual-disability-in-mouse-with-phenylketonuria
#14
Tiziana Pascucci, Luigia Rossi, Marco Colamartino, Claudia Gabucci, Claudia Carducci, Alessandro Valzania, Valeria Sasso, Noemi Bigini, Francesca Pierigè, Maria Teresa Viscomi, Rossella Ventura, Simona Cabib, Mauro Magnani, Stefano Puglisi-Allegra, Vincenzo Leuzzi
Untreated phenylketonuria (PKU) results in severe neurodevelopmental disorders, which can be partially prevented by an early and rigorous limitation of phenylalanine (Phe) intake. Enzyme substitution therapy with recombinant Anabaena variabilis Phe Ammonia Lyase (rAvPAL) proved to be effective in reducing blood Phe levels in preclinical and clinical studies of adults with PKU. Aims of present study were: a) to gather proofs of clinical efficacy of rAvPAL treatment in preventing neurological impairment in an early treated murine model of PKU; b) to test the advantages of an alternative delivering system for rAvPAL such as autologous erythrocytes...
April 7, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29685658/novel-founder-intronic-variant-in-slc39a14-in-two-families-causing-manganism-and-potential-treatment-strategies
#15
Lance H Rodan, Marissa Hauptman, Alissa M D'Gama, Anita E Qualls, Siqi Cao, Karin Tuschl, Fatma Al-Jasmi, Jozef Hertecant, Susan J Hayflick, Marianne Wessling-Resnick, Edward T Yang, Gerard T Berry, Andrea Gropman, Alan D Woolf, Pankaj B Agrawal
Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing...
April 6, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29653686/pegvaliase-for-the-treatment-of-phenylketonuria-results-of-a-long-term-phase-3-clinical-trial-program-prism
#16
Janet Thomas, Harvey Levy, Stephen Amato, Jerry Vockley, Roberto Zori, David Dimmock, Cary O Harding, Deborah A Bilder, Haoling H Weng, Joy Olbertz, Markus Merilainen, Joy Jiang, Kevin Larimore, Soumi Gupta, Zhonghua Gu, Hope Northrup
BACKGROUND: Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Two Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU...
March 31, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29680633/multiplex-tandem-mass-spectrometry-assay-for-newborn-screening-of-x-linked-adrenoleukodystrophy-biotinidase-deficiency-and-galactosemia-with-flexibility-to-assay-other-enzyme-assays-and-biomarkers
#17
Xinying Hong, Arun Babu Kumar, C Ronald Scott, Michael H Gelb
All States screen for biotinidase deficiency and galactosemia, and X-linked adrenoleukodystrophy (X-ALD) has recently been added to the Recommended Uniform Screening Panel (RUSP).We sought to consolidate these tests by combining them into a single multiplex tandem mass spectrometry assay as well as to improve the current protocol for newborn screening of galactosemia.A 3 mm punch of a dried blood spot (DBS) was extracted with organic solvent for analysis of the C26:0-lysophosphatidylcholine biomarker for X-ALD...
March 29, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29655841/lysosomal-acid-lipase-deficiency-allograft-recurrence-and-liver-failure-clinical-outcomes-of-18-liver-transplantation-patients
#18
REVIEW
Donna Lee Bernstein, Steven Lobritto, Alina Iuga, Helen Remotti, Thomas Schiano, Maria Isabel Fiel, Manisha Balwani
Lysosomal acid lipase deficiency (LAL-D) results in progressive microvesicular hepatosteatosis, fibrosis, cirrhosis, dyslipidemia, and vascular disease. Interventions available prior to enzyme replacement therapy development, including lipid lowering medications, splenectomy, hematopoietic stem cell and liver transplantation were unsuccessful at preventing multi-systemic disease progression, and were associated with significant morbidity and mortality. We report two sisters, diagnosed in infancy, who succumbed to LAL-D with accelerated disease progression following splenectomy and liver transplantation...
March 27, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29602698/novel-insights-into-the-functional-metabolic-impact-of-an-apparent-de-novo-m-8993t-g-variant-in-the-mt-atp6-gene-associated-with-maternally-inherited-form-of-leigh-syndrome
#19
Martine Uittenbogaard, Christine A Brantner, ZiShui Fang, Lee-Jun C Wong, Andrea Gropman, Anne Chiaramello
In this study, we report a novel perpective of metabolic consequences for the m.8993T>G variant using fibroblasts from a proband with clinical symptoms compatible with Maternally Inherited Leigh Syndrome (MILS). Definitive diagnosis was corroborated by mitochondrial DNA testing for the pathogenic variant m.8993T>G in MT-ATP6 subunit by Sanger sequencing. The long-range PCR followed by massively parallel sequencing method detected the near homoplasmic m.8993T>G variant at 83% in the proband's fibroblasts and at 0...
March 27, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29580649/recommendations-for-newborn-screening-for-galactokinase-deficiency-a-systematic-review-and-evaluation-of-dutch-newborn-screening-data
#20
Kevin Stroek, Marelle J Bouva, Peter C J I Schielen, Frédéric M Vaz, Annemieke C Heijboer, Robert de Jonge, Anita Boelen, Annet M Bosch
INTRODUCTION: Galactokinase (GALK) deficiency causes cataract leading to severe developmental consequences unless treated early. Because of the easy prevention and rapid reversibility of cataract with treatment, the Dutch Health Council advised to include GALK deficiency in the Dutch newborn screening program. The aim of this study is to establish the optimal screening method and cut-off value (COV) for GALK deficiency screening by performing a systematic review of the literature of screening strategies and total galactose (TGAL) values and by evaluating TGAL values in the first week of life in a cohort of screened newborns in the Netherlands...
March 21, 2018: Molecular Genetics and Metabolism
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