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Classical homocystinuria

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https://www.readbyqxmd.com/read/29119254/potential-pharmacological-chaperones-for-cystathionine-beta-synthase-deficient-homocystinuria
#1
Tomas Majtan, Angel L Pey, Paula Gimenez-Mascarell, Luis Alfonso Martínez-Cruz, Csaba Szabo, Viktor Kožich, Jan P Kraus
Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine beta-synthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form nonfunctional aggregates or to undergo proteasome-dependent degradation...
November 10, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29101223/taurine-treatment-prevents-derangement-of-the-hepatic-%C3%AE-glutamyl-cycle-and-methylglyoxal-metabolism-in-a-mouse-model-of-classical-homocystinuria-regulatory-crosstalk-between-thiol-and-sulfinic-acid-metabolism
#2
Kenneth N Maclean, Hua Jiang, Stefanos Aivazidis, Eugene Kim, Colin T Shearn, Peter S Harris, Dennis R Petersen, Robert H Allen, Sally P Stabler, James R Roede
Cystathionine β-synthase-deficient homocystinuria (HCU) is a poorly understood, life-threatening inborn error of sulfur metabolism. Analysis of hepatic glutathione (GSH) metabolism in a mouse model of HCU demonstrated significant depletion of cysteine, GSH, and GSH disulfide independent of the block in trans-sulfuration compared with wild-type controls. HCU induced the expression of the catalytic and regulatory subunits of γ-glutamyl ligase, GSH synthase (GS), γ-glutamyl transpeptidase 1, 5-oxoprolinase (OPLAH), and the GSH-dependent methylglyoxal detoxification enzyme, glyoxalase-1...
November 3, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29044829/enzyme-replacement-therapy-prevents-loss-of-bone-and-fat-mass-in-murine-homocystinuria
#3
Tomas Majtan, Insun Park, Erez M Bublil, Jan P Kraus
Skeletal and connective tissue defects are the most striking symptoms in patients suffering from classical homocystinuria (HCU). Here, we determined body composition and bone mass in three mouse models of HCU and assessed whether a long-term administration of enzyme replacement therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dual-energy X-ray absorptiometry and the data were complemented by plasma biochemical profiles. Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on a mouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due to a lower fat content compared with negative controls...
October 16, 2017: Human Mutation
https://www.readbyqxmd.com/read/28821635/enzyme-replacement-prevents-neonatal-death-liver-damage-and-osteoporosis-in-murine-homocystinuria
#4
Tomas Majtan, Helena Hůlková, Insun Park, Jakub Krijt, Viktor Kožich, Erez M Bublil, Jan P Kraus
Classical homocystinuria (HCU) is an inborn error of sulfur amino acid metabolism caused by deficient activity of cystathionine β-synthase (CBS), resulting in an accumulation of homocysteine and a concomitant decrease of cystathionine and cysteine in blood and tissues. In mice, the complete lack of CBS is neonatal lethal. In this study, newborn CBS knockout (KO) mice were treated with recombinant polyethyleneglycolylated human truncated CBS (PEG-CBS). Full survival of the treated KO mice, along with a positive impact on metabolite levels in plasma, liver, brain, and kidneys, was observed...
August 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28801090/leptin-concentrations-and-scd-1-indices-in-classical-homocystinuria-evidence-for-the-role-of-sulfur-amino-acids-in-the-regulation-of-lipid-metabolism
#5
Soraia Poloni, Poli Mara Spritzer, Roberta H Mendes, Vânia D'Almeida, Kamila Castro, Fernanda Sperb-Ludwig, Johanna Kugele, Sara Tucci, Henk J Blom, Ida V D Schwartz
BACKGROUND: We describe body composition, lipid metabolism and Stearoyl-CoA desaturase-1 (SCD-1) indices in patients with classical homocystinuria (HCU). METHODS: Eleven treated HCU patients and 16 healthy controls were included. Body composition and bone mineral density were assessed by dual X-ray absorptiometry. Sulfur amino acids (SAA) and their derivatives (total homocysteine, cysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, and glutathione), lipids (free fatty acids, acylcarnitines, triglycerides and lipoproteins), glucose, insulin, leptin, adiponectin, and isoprostanes were measured in plasma...
October 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28779878/adult-classical-homocystinuria-requiring-parenteral-nutrition-pitfalls-and-management
#6
REVIEW
Christel Tran, Luisa Bonafé, Jean-Marc Nuoffer, Julie Rieger, Mette M Berger
BACKGROUND: Homocystinuria due to cystathionine beta synthase (CBS) deficiency presents with a wide clinical spectrum. Treatment by the enteral route aims at reducing homocysteine levels by using vitamin B6, possibly methionine-restricted diet, betaine and/or folate and vitamin B12 supplementation. Currently no nutritional guidelines exist regarding parenteral nutrition (PN) under acute conditions. METHODS: Exhaustive literature search was performed, in order to identify the relevant studies describing the pathogenesis and nutritional intervention of adult classical homocystinuria requiring PN...
July 25, 2017: Clinical Nutrition: Official Journal of the European Society of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28583326/cystathionine-%C3%AE-synthase-deficiency-of-mice-and-men
#7
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...
July 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28488385/the-c-797-g-a-p-r266k-cystathionine-%C3%AE-synthase-mutation-causes-homocystinuria-by-affecting-protein-stability
#8
Sapna Gupta, Liqun Wang, Warren D Kruger
Mutations in the cystathionine beta-synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The c.797 G>A (p.R266K) mutation in CBS was originally described in several Norwegian pyridoxine responsive CBS deficient patients, and heterologous gene expression studies have shown that the protein has near wild-type levels of enzyme activity. Here, we characterize a transgenic mouse lacking endogenous Cbs and expressing p.R266K human CBS protein from a zinc inducible metallothionein promoter (Tg-R266K Cbs(-/-) )...
July 2017: Human Mutation
https://www.readbyqxmd.com/read/28473367/malar-rash-in-classical-homocystinuria
#9
Arushi Gahlot Saini, Hansashree Padmanabha, Savita Attri, Pratibha Singhi
No abstract text is available yet for this article.
May 3, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28431470/engineering-and-characterization-of-an-enzyme-replacement-therapy-for-classical-homocystinuria
#10
Tomas Majtan, Insun Park, Richard S Carrillo, Erez M Bublil, Jan P Kraus
Homocystinuria due to loss of cystathionine beta-synthase (CBS) causes accumulation of homocysteine and depletion of cysteine. Current treatments are suboptimal, and thus the development of an enzyme replacement therapy based on PEGylated human truncated CBS (PEG-CBS) has been initiated. Attenuation of potency was observed, which necessitated a screen of several PEG-CBS conjugates for their efficacy to correct and maintain the plasma metabolite profile of murine homocystinuria after repeated administrations interrupted with washouts...
May 1, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28421128/a-clinically-relevant-variant-of-the-human-hydrogen-sulfide-synthesizing-enzyme-cystathionine-%C3%AE-synthase-increased-co-reactivity-as-a-novel-molecular-mechanism-of-pathogenicity
#11
João B Vicente, Henrique G Colaço, Francesca Malagrinò, Paulo E Santo, André Gutierres, Tiago M Bandeiras, Paula Leandro, José A Brito, Alessandro Giuffrè
The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5'-phosphate- (PLP-) dependent cystathionine β-synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (H2S). CBS activity, contributing to cellular redox homeostasis, is positively regulated by S-adenosyl-L-methionine (AdoMet) but fully inhibited upon CO or NO• binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenic CBS mutations is not yet fully understood...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28291718/cystathionine-beta-synthase-deficiency-alters-hepatic-phospholipid-and-choline-metabolism-post-translational-repression-of-phosphatidylethanolamine-n-methyltransferase-is-a-consequence-rather-than-a-cause-of-liver-injury-in-homocystinuria
#12
René L Jacobs, Hua Jiang, John P Kennelly, David J Orlicky, Robert H Allen, Sally P Stabler, Kenneth N Maclean
Classical homocystinuria (HCU) due to inactivating mutation of cystathionine β-synthase (CBS) is a poorly understood life-threatening inborn error of sulfur metabolism. A previously described cbs-/- mouse model exhibits a semi-lethal phenotype due to neonatal liver failure. The transgenic HO mouse model of HCU exhibits only mild liver injury and recapitulates multiple aspects of the disease as it occurs in humans. Disruption of the methionine cycle in HCU has the potential to impact multiple aspect of phospholipid (PL) metabolism by disruption of both the Kennedy pathway and phosphatidylethanolamine N-methyltransferase (PEMT) mediated synthesis of phosphatidylcholine (PC)...
April 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28137899/cerebral-venous-thrombosis-as-the-first-presentation-of-classical-homocystinuria-in-an-adult-patient
#13
Emily Woods, Charlotte Dawson, Latha Senthil, Tarekegn Geberhiwot
A 30-year-old woman presented with severe headache, dysarthria and right hemiparesis. She was treated for suspected viral encephalopathy and recovered over the following weeks although the headaches persisted. Two months later she was treated in-hospital for pulmonary embolism. The following year she was readmitted for increased frequency of headaches and was given a diagnosis of migraine. A subsequent MRI head scan was suggestive of longstanding venous sinus infarcts and neuroradiology review concluded that encephalitis had been the incorrect initial diagnosis...
January 30, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28101774/newborn-screening-for-remethylation-disorders-and-vitamin-b12-deficiency-evaluation-of-new-strategies-in-cohorts-from-qatar-and-germany
#14
Gwendolyn Gramer, Ghassan Abdoh, Tawfeg Ben-Omran, Noora Shahbeck, Rehab Ali, Laila Mahmoud, Junmin Fang-Hoffmann, Georg F Hoffmann, Hilal Al Rifai, Jürgen G Okun
BACKGROUND: Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-ß-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar. METHODS: A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine-ratio and propionylcarnitine as second-tiers...
April 2017: World Journal of Pediatrics: WJP
https://www.readbyqxmd.com/read/27681349/peripheral-nerve-involvement-in-classic-homocystinuria-an-unusual-association
#15
Miguel Oliveira Santos, Ruth Geraldes, Isabel Conceição
Classic homocystinuria is one of the most common causes of hereditary hyperhomocysteinemia. It is an autosomal recessive and multisystemic disorder due to cystathionine β-synthase deficiency. We described a case of an 18-year-old Portuguese man with an ischaemic stroke, who was subsequently diagnosed with classic homocystinuria [Thr191Met (c.572C>T) CBS mutation] associated with a sensorimotor neuropathy. The patient had a good clinical and metabolic response to pyridoxine plus methionine-restricted diet after 12 months of treatment...
2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27325427/newborn-screening-for-vitamin-b6-non-responsive-classical-homocystinuria-systematical-evaluation-of-a-two-tier-strategy
#16
Jürgen G Okun, Hongying Gan-Schreier, Tawfeq Ben-Omran, Kathrin V Schmidt, Junmin Fang-Hoffmann, Gwendolyn Gramer, Ghassan Abdoh, Noora Shahbeck, Hilal Al Rifai, Abdul Latif Al Khal, Gisela Haege, Chuan-Chi Chiang, David C Kasper, Bridget Wilcken, Peter Burgard, Georg F Hoffmann
BACKGROUND: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening. METHODS: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies...
2017: JIMD Reports
https://www.readbyqxmd.com/read/27183384/vision-of-correction-for-classic-homocystinuria
#17
Dwight D Koeberl
Inherited metabolic disorders are often characterized by the lack of an essential enzyme and are currently treated by dietary restriction and other strategies to replace the substrates or products of the missing enzyme. Patients with homocystinuria lack the enzyme cystathionine β-synthase (CBS), and many of these individuals do not respond to current treatment protocols. In this issue of the JCI, Bublil and colleagues demonstrate that enzyme replacement therapy (ERT) provides long-term amelioration of homocystinuria-associated phenotypes in CBS-deficient murine models...
June 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/26931358/targeting-cystathionine-beta-synthase-misfolding-in-homocystinuria-by-small-ligands-state-of-the-art-and-future-directions
#18
REVIEW
Tomas Majtan, Angel L Pey, June Ereño-Orbea, Luis Alfonso Martínez-Cruz, Jan P Kraus
Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acids metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine betasynthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form non-functional aggregates or to undergo proteasome-dependent degradation...
2016: Current Drug Targets
https://www.readbyqxmd.com/read/26791043/thioethers-as-markers-of-hydrogen-sulfide-production-in-homocystinurias
#19
Viktor Kožich, Jakub Krijt, Jitka Sokolová, Petra Melenovská, Pavel Ješina, Roman Vozdek, Tomáš Majtán, Jan P Kraus
Two enzymes in the transsulfuration pathway of homocysteine -cystathionine beta-synthase (CBS) and gamma-cystathionase (CTH)-use cysteine and/or homocysteine to produce the important signaling molecule hydrogen sulfide (H2S) and simultaneously the thioethers lanthionine, cystathionine or homolanthionine. In this study we explored whether impaired flux of substrates for H2S synthesis and/or deficient enzyme activities alter production of hydrogen sulfide in patients with homocystinurias. As an indirect measure of H2S synthesis we determined by LC-MS/MS concentrations of thioethers in plasma samples from 33 patients with different types of homocystinurias, in 8 patient derived fibroblast cell lines, and as reaction products of seven purified mutant CBS enzymes...
July 2016: Biochimie
https://www.readbyqxmd.com/read/26639091/successive-mri-findings-of-reversible-cerebral-white-matter-lesions-in-a-patient-with-cystathionine-%C3%AE-synthase-deficiency
#20
Hideo Sasai, Nobuyuki Shimozawa, Takahiko Asano, Norio Kawamoto, Takahiro Yamamoto, Takeshi Kimura, Minako Kawamoto, Eiko Matsui, Toshiyuki Fukao
Cystathionine β-synthase (CBS) deficiency, well known as classical homocystinuria, is a rare autosomal recessive inborn error of homocysteine and sulfur metabolism. CBS converts homocysteine to cystathionine. The clinical features of untreated CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Cerebral white matter lesions (CWMLs), identified in magnetic resonance imaging (MRI), are related to various clinical conditions including ischemia, inflammation, demyelination, infection, a tumor, and metabolic disorders such as phenylketonuria...
December 2015: Tohoku Journal of Experimental Medicine
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