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Inborn errors of metabolism

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https://www.readbyqxmd.com/read/29453510/next-generation-metabolic-screening-targeted-and-untargeted-metabolomics-for-the-diagnosis-of-inborn-errors-of-metabolism-in-individual-patients
#1
Karlien L M Coene, Leo A J Kluijtmans, Ed van der Heeft, Udo F H Engelke, Siebolt de Boer, Brechtje Hoegen, Hanneke J T Kwast, Maartje van de Vorst, Marleen C D G Huigen, Irene M L W Keularts, Michiel F Schreuder, Clara D M van Karnebeek, Saskia B Wortmann, Maaike C de Vries, Mirian C H Janssen, Christian Gilissen, Jasper Engel, Ron A Wevers
The implementation of whole-exome sequencing in clinical diagnostics has generated a need for functional evaluation of genetic variants. In the field of inborn errors of metabolism (IEM), a diverse spectrum of targeted biochemical assays is employed to analyze a limited amount of metabolites. We now present a single-platform, high-resolution liquid chromatography quadrupole time of flight (LC-QTOF) method that can be applied for holistic metabolic profiling in plasma of individual IEM-suspected patients. This method, which we termed "next-generation metabolic screening" (NGMS), can detect >10,000 features in each sample...
February 16, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29445992/the-functional-genomics-laboratory-functional-validation-of-genetic-variants
#2
Richard J Rodenburg
Currently, one of the main challenges in human molecular genetics is the interpretation of rare genetic variants of unknown clinical significance. A conclusive diagnosis is of importance for the patient to obtain certainty about the cause of the disease, for the clinician to be able to provide optimal care to the patient and to predict the disease course, and for the clinical geneticist for genetic counseling of the patient and family members. Conclusive evidence for pathogenicity of genetic variants is therefore crucial...
February 14, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29445937/secondary-hemophagocytic-syndrome-associated-with-cog6-gene-defect-report-and-review
#3
Nouf Althonaian, Abdulrahman Alsultan, Eva Morava, Majid Alfadhel
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Clinically, it is characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. It can be classified as primary if it is due to a genetic defect, or secondary if it is due to a different etiology such as severe infection, immune deficiency syndrome, rheumatological disorder, malignancy, and inborn errors of metabolism such as galactosemia, multiple sulfatase deficiency, lysinuric protein intolerance, Gaucher disease, Niemann-Pick disease, Wolman disease, propionic acidemia, methylmalonic acidemia, biotinidase deficiency, cobalamin C defect, galactosialidosis, Pearson syndrome, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency...
February 15, 2018: JIMD Reports
https://www.readbyqxmd.com/read/29443755/argininemia-as-a-cause-of-severe-chronic-stunting-and-partial-growth-hormone-deficiency-pghd-a-case-report
#4
Xiaotang Cai, Dan Yu, Yongmei Xie, Hui Zhou
RATIONALE: Argininemia is an autosomal recessive inherited disorder of the urea cycle. Because of its atypical symptoms in early age, diagnosis can be delayed until the typical chronic manifestations - including spastic diplegia, deterioration in cognitive function, and epilepsy - appear in later childhood. PATIENT CONCERNS: A Chinese boy initially presented with severe stunting and partial growth hormone deficiency (PGHD) at 3 years old and was initially treated with growth hormone replacement therapy...
February 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29437538/leveraging-rational-protein-engineering-to-improve-mrna-therapeutics
#5
Jeremiah D Farelli, Kirtika H Asrani, Cleo Isaacs, Joanna S deBear, Mary R Stahley, Anumeha Shah, Melissa A Lasaro, Christopher J Cheng, Romesh R Subramanian
Messenger RNA (mRNA) is a promising new class of therapeutics that has potential for treatment of diseases in fields such as immunology, oncology, vaccines, and inborn errors of metabolism. mRNA therapy has several advantages over DNA-based gene therapy, including the lack of the need for nuclear import and transcription, as well as limited possibility of genomic integration. One drawback of mRNA therapy, especially in cases such as metabolic disorders where repeated dosing will be necessary, is the relatively short in vivo half-life of mRNA (∼6-12 h)...
February 13, 2018: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29435782/insulin-resistance-in-glycogen-storage-disease-type-ia-linking-carbohydrates-and-mitochondria
#6
Alessandro Rossi, Margherita Ruoppolo, Pietro Formisano, Guglielmo Villani, Lucia Albano, Giovanna Gallo, Daniela Crisci, Augusta Moccia, Giancarlo Parenti, Pietro Strisciuglio, Daniela Melis
BACKGROUND: Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). GSDIa patients are at higher risk of developing insulin-resistance (IR). Mitochondrial dysfunction has been implicated in the development of IR. Mitochondrial dysfunction can demonstrate abnormalities in plama acylcarnitines (ACs) and urine organic acids (UOA). The aim of the study was to investigate the presence of mitochondrial impairment in GSDI patients and its possible connection with IR...
February 12, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29435781/fast-and-accurate-quantitative-organic-acid-analysis-with-lc-qtof-ms-facilitates-screening-of-patients-for-inborn-errors-of-metabolism
#7
Irene M L W Körver-Keularts, Ping Wang, Huub W A H Waterval, Leo A J Kluijtmans, Ron A Wevers, Claus-Dieter Langhans, Camilla Scott, Daphna D J Habets, Jörgen Bierau
Since organic acid analysis in urine with gaschromatography-mass spectrometry (GC-MS) is a time-consuming technique, we developed a new liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) method to replace the classical analysis for diagnosis of inborn errors of metabolism (IEM). Sample preparation is simple and experimental time short. Targeted mass extraction and automatic calculation of z-scores generated profiles characteristic for the IEMs in our panel consisting of 71 biomarkers for defects in amino acids, neurotransmitters, fatty acids, purine, and pyrimidine metabolism as well as other disorders...
February 12, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29432237/hypoxic-ischemic-encephalopathy-and-other-neonatal-encephalopathies
#8
Hannah C Glass
PURPOSE OF REVIEW: Neonatal encephalopathy is the most common condition in neonates encountered by child neurologists. The etiology is most often global hypoxia-ischemia due to failure of cerebral perfusion to the fetus caused by uterine, placental, or umbilical cord compromise prior to or during delivery. Other etiologies of neonatal encephalopathy include ischemic stroke and intracranial hemorrhage, infection, developmental anomalies, and inborn errors of metabolism. RECENT FINDINGS: Therapeutic hypothermia is standard of care for the treatment of neonatal encephalopathy presumed to be caused by hypoxia-ischemia...
February 2018: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/29432236/testing-for-inborn-errors-of-metabolism
#9
Jennifer M Kwon
PURPOSE OF REVIEW: This article provides an overview of genetic metabolic disorders that can be identified by metabolic tests readily available to neurologists, such as tests for ammonia, plasma amino acids, and urine organic acids. The limitations of these tests are also discussed, as they only screen for a subset of the many inborn errors of metabolism that exist. RECENT FINDINGS: Advances in next-generation sequencing and the emerging use of advanced metabolomic screening have made it possible to diagnose treatable inborn errors of metabolism that are not included in current newborn screening programs...
February 2018: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/29429868/from-rodent-heart-to-inborn-errors-of-human-metabolism
#10
Jörn Oliver Sass, Sema Kalkan Uçar, Clara D M van Karnebeek
No abstract text is available yet for this article.
February 5, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29417439/antioxidants-reverse-the-changes-in-the-cholinergic-system-caused-by-l-tyrosine-administration-in-rats
#11
Lara M Gomes, Giselli Scaini, Milena Carvalho-Silva, Maria L Gomes, Fernanda Malgarin, Luiza W Kist, Maurício R Bogo, Eduardo Pacheco Rico, Alexandra I Zugno, Pedro F P Deroza, Gislaine Z Réus, Airam B de Moura, João Quevedo, Gustavo C Ferreira, Patrícia F Schuck, Emilio L Streck
Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in the activity of the enzyme tyrosine aminotransferase, leading to tyrosine accumulation in the body. Although the mechanisms involved are still poorly understood, several studies have showed that higher levels of tyrosine are related to oxidative stress and therefore may affect the cholinergic system. Thus, the aim of this study was to investigate the effects of chronic administration of L-tyrosine on choline acetyltransferase activity (ChAT) and acetylcholinesterase (AChE) in the brain of rats...
February 7, 2018: Neurotoxicity Research
https://www.readbyqxmd.com/read/29413985/beyond-the-limit-of-assignment-of-metabolites-using-minimal-serum-samples-and-1h-nmr-spectroscopy-with-cross-validation-by-mass-spectrometry
#12
Ashish Gupta, Deepak Kumar
Identification of NMR-based metabolic indexes is limited by the deleterious effects of copious proteins and lipoproteins in the serum that accentuate the need for advance and high-throughput method. We tried to explore the use of a novel filtration (2KDa molecular weight cut-off) approach to remove the proteins from serum following use of less sample volume (only 150 μL of filtered serum), combining an array of 1D/2D NMR experiments (at 800 MHz spectrometer), spiking experiments with standard compounds, and validated by mass spectrometry...
January 9, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29409891/hereditary-galactosemia
#13
REVIEW
Didem Demirbas, Ana I Coelho, M Estrela Rubio-Gozalbo, Gerard T Berry
Hereditary galactosemia is an inborn error of carbohydrate metabolism. Galactose is metabolized by Leloir pathway enzymes; galactokinase (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). The defects in these enzymes cause galactosemia in an autosomal recessive manner. The common and severe GALT deficiency, or classic galactosemia, is life-threatening in the newborn period. The treatment for classic galactosemia is dietary restriction of lactose. Although implementation of lactose restricted diet is efficient in resolving the acute complications, it is not sufficient to prevent long-term complications affecting the brain and female gonads, the two main target organs of damage...
January 30, 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29404805/inborn-errors-of-metabolism-and-the-human-interactome-a-systems-medicine-approach
#14
Mathias Woidy, Ania C Muntau, Søren W Gersting
The group of inborn errors of metabolism (IEM) displays a marked heterogeneity and IEM can affect virtually all functions and organs of the human organism; however, IEM share that their associated proteins function in metabolism. Most proteins carry out cellular functions by interacting with other proteins, and thus are organized in biological networks. Therefore, diseases are rarely the consequence of single gene mutations but of the perturbations caused in the related cellular network. Systematic approaches that integrate multi-omics and database information into biological networks have successfully expanded our knowledge of complex disorders but network-based strategies have been rarely applied to study IEM...
February 5, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29402417/a-novel-method-for-quantitation-of-acylglycines-in-human-dried-blood-spots-by-uplc-tandem-mass-spectrometry
#15
Lawrence Fisher, Christine Davies, Osama Y Al-Dirbashi, Herman J Ten Brink, Pranesh Chakraborty, Nathalie Lepage
BACKGROUND: Several acylcarnitines used as primary markers on dried blood filter papers (DBS) for newborn screening lack specificity and contribute to a higher false positive rate. The analysis of urine acylglycines is useful in the diagnosis of inborn errors of metabolism (IEM) including medium chain acyl-CoA dehydrogenase deficiency (MCADD), isovaleric acidemia, and beta-ketothiolase deficiency (BKTD). Currently, no method for analyzing acylglycines from DBS has been published. METHODS: Acylglycines were extracted from two 3...
February 2, 2018: Clinical Biochemistry
https://www.readbyqxmd.com/read/29401530/antiquitin-deficiency-with-adolescent-onset-epilepsy-molecular-diagnosis-in-a-mother-of-affected-offsprings
#16
Rangan Srinivasaraghavan, Narayanan Parameswaran, Deborah Mathis, Celine Bürer, Barbara Plecko
Antiquitin deficiency is the most prevalent form of pyridoxine-dependent epilepsy. While most patients present with neonatal onset of therapy-resistant seizures, a few cases with late-onset during infancy have been described. Here, we describe the juvenile onset of epilepsy at the age of 17 years due to antiquitin deficiency in an Indian female with homozygosity for the most prevalent ALDH7A1 missense mutation, c.1279G > C; p.Glu427Gln in exon 14. The diagnosis was established along familial cosegregation analysis for an affected offspring, that had neonatal pyridoxine responsive seizures and had been found to be compound heterozygous for c...
February 5, 2018: Neuropediatrics
https://www.readbyqxmd.com/read/29397479/identifying-and-addressing-genetic-counseling-challenges-among-indigenous-people-of-oaxaca-one-center-s-experience-with-two-immigrant-farmworker-families-in-the-central-valley-of-california
#17
Joseph J Shen, Jason Carmichael, Leoncio Vásquez Santos
An important aspect of genetic counseling is the recognition of and adaptation to the socio-cultural uniqueness of the different populations that a genetics clinic serves. The Central Valley of California is home to a large population from Mexico, with a significant proportion of indigenous ancestry originating from the state of Oaxaca. We report on our experience with two families of this community-one extended family with an early lethal inborn error of metabolism and the other with a chronic disfiguring form of ichthyosis...
February 3, 2018: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/29397027/hereditary-palmoplantar-keratodermas-part-ii-syndromic-palmoplantar-keratodermas-diagnostic-algorithm-and-principles-of-therapy
#18
REVIEW
L Guerra, M Castori, B Didona, D Castiglia, G Zambruno
Hereditary palmoplantar keratodermas (PPKs) comprise a large and heterogeneous group of disorders characterized by persistent thickening of the epidermis at palmar and plantar surfaces. Clinical and genetic features of isolated and complex PPKs have been reviewed in part I of this 2-part review. Here we focus on clinical and molecular classification of syndromic PPKs which are recognized by additional extracutaneous manifestations, in particular deafness, specific mucosal lesions, cardiomyopathy, inborn errors of metabolism, involvement of internal organs or disorders of sexual development...
February 3, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29396939/creatine-transporter-deficiency-in-two-brothers-with-autism-spectrum-disorder
#19
Halil Ibrahim Aydin
BACKGROUND: Creatine transporter deficiency (CTD) is a treatable, X-linked, inborn error of metabolism. CASE CHARACTERISTICS: Two brothers with autism spectrum disorder were diagnosed with CTD at the ages of 17 and 12 years. Both were found to have a previously reported hemizygous p.408delF (c.1216_1218delTTC) deletion mutation. OUTCOME: Both patients were given creatine monohydrate, L-arginine, L-glycine and S-adenosylmethionine, which partially improved the behavioral problems...
January 15, 2018: Indian Pediatrics
https://www.readbyqxmd.com/read/29396136/renal-replacement-therapy-in-the-neonatal-intensive-care-unit
#20
Tze Yee Diane Mok, Min-Hua Tseng, Ming-Chou Chiang, Ju-Li Lin, Shih Ming Chu, Jen-Fu Hsu, Reyin Lien
BACKGROUND: Renal replacement therapy (RRT) is becoming increasingly necessary for supporting critically ill neonates. Few studies have reported the use of RRT in the neonatal intensive care unit (NICU). Therefore, we performed a retrospective study to describe the use of RRT in our NICU and its associated efficacy, complications, and outcomes. METHODS: We identified patients requiring RRT between January 2009 and January 2017. Demographic data, mode of RRT, and associated factors were recorded...
December 21, 2017: Pediatrics and Neonatology
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