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Search on : Homocystinuria [Words]
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[PMID]: 29398487
[Au] Autor:Majtan T; Jones W; Krijt J; Park I; Kruger WD; Kozich V; Bassnett S; Bublil EM; Kraus JP
[Ad] Address:Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: tomas.majtan@ucdenver.edu.
[Ti] Title:Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria.
[So] Source:Mol Ther;26(3):834-844, 2018 Mar 07.
[Is] ISSN:1525-0024
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Classical homocystinuria (HCU) is the most common inherited disorder of sulfur amino acid metabolism caused by deficiency in cystathionine beta-synthase (CBS) activity and characterized by severe elevation of homocysteine in blood and tissues. Treatment with dietary methionine restriction is not optimal, and poor compliance leads to serious complications. We developed an enzyme replacement therapy (ERT) and studied its efficacy in a severe form of HCU in mouse (the I278T model). Treatment was initiated before or after the onset of clinical symptoms in an effort to prevent or reverse the phenotype. ERT substantially reduced and sustained plasma homocysteine concentration at around 100 µM and normalized plasma cysteine for up to 9 months of treatment. Biochemical balance was also restored in the liver, kidney, and brain. Furthermore, ERT corrected liver glucose and lipid metabolism. The treatment prevented or reversed facial alopecia, fragile and lean phenotype, and low bone mass. In addition, structurally defective ciliary zonules in the eyes of I278T mice contained low density and/or broken fibers, while administration of ERT from birth partially rescued the ocular phenotype. In conclusion, ERT maintained an improved metabolic pattern and ameliorated many of the clinical complications in the I278T mouse model of HCU.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review

  2 / 2075 MEDLINE  
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[PMID]: 29508359
[Au] Autor:Li DX; Li XY; Dong H; Liu YP; Ding Y; Song JQ; Jin Y; Zhang Y; Wang Q; Yang YL
[Ad] Address:Department of Pediatrics, Peking University First Hospital, No. 1 Xi'anmen Street, West District, Beijing, 100034, China.
[Ti] Title:Eight novel mutations of CBS gene in nine Chinese patients with classical homocystinuria.
[So] Source:World J Pediatr;, 2018 Mar 05.
[Is] ISSN:1867-0687
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:BACKGROUND: Classical homocystinuria (homocysteinemia type 1, MIM# 236200) is a rare inherited disorder in Mainland China. This study aimed to identify mutations in the cystathionine ß-synthase (CBS) gene which are associated with classical homocystinuria in nine Chinese patients. METHODS: Nine Chinese patients were diagnosed at the age of 5 years 4 months to 18 years by plasma total homocysteine and blood methionine determination. CBS gene analysis was performed for the patients and their families. RESULTS: All nine patients had significantly increased plasma total homocysteine (142-500 µmol/L vs. the normal range of 0-15 µmol/L) and blood methionine (144.3-500 µmol/L vs. the normal range of 0-50 µmol/L). None of the patients was pyridoxine responsive. Eleven mutations in CBS gene were identified in the nine patients. Eight mutations (IVS3+1G>A, p.Thr493fsX46, p.Thr236Asn, p.Leu230Gln, p.Lys72Ile, p.Ser201ProfsX36, p.Met337IlefsX115, and IVS14-1G>C) were novel. Three mutations (p.Arg125Gln, p.Thr257Met and p.Gly116Arg) had been previously reported. CONCLUSIONS: In this study, eight novel mutations in CBS were identified in nine Chinese patients with classical homocystinuria. None of the hotspot mutations reported in other regions previously was found. These data indicated that Chinese maybe had different CBS mutation spectrum from other population. The identification of mutations not only confirms the diagnosis but also enables accurate genetic counselling and prenatal diagnosis for the fetuses of the families.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180306
[Lr] Last revision date:180306
[St] Status:Publisher
[do] DOI:10.1007/s12519-018-0135-9

  3 / 2075 MEDLINE  
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[PMID]: 29502913
[Au] Autor:Sklirou E; Lichter-Konecki U
[Ad] Address:Division of Medical Genetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
[Ti] Title:Inborn Errors of Metabolism with Cognitive Impairment: Metabolism Defects of Phenylalanine, Homocysteine and Methionine, Purine and Pyrimidine, and Creatine.
[So] Source:Pediatr Clin North Am;65(2):267-277, 2018 Apr.
[Is] ISSN:1557-8240
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Phenylketonuria is a defect in phenylalanine metabolism resulting in the excretion of phenylketones and severe intellectual disability. The principle of eliminating the offending amino acid from the diet as a successful treatment strategy was demonstrated. The development of a low methionine diet to treat homocystinuria was established after identifying the transsulfuration pathway resulting in cysteine synthesis. Both conditions are examples of disorders of amino acid metabolism. Lesch-Nyhan syndrome, a rare disorder of purine metabolism resulting in intellectual disability and self-injurious behavior, is a classical inborn error of metabolism. Disorders of creatine biosynthesis are relatively newly described and less known diseases.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[St] Status:In-Data-Review

  4 / 2075 MEDLINE  
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[PMID]: 29275181
[Au] Autor:Giménez-Mascarell P; Majtan T; Oyenarte I; Ereño-Orbea J; Majtan J; Klaudiny J; Kraus JP; Martínez-Cruz LA
[Ad] Address:Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC Biogune), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
[Ti] Title:Crystal structure of cystathionine ß-synthase from honeybee Apis mellifera.
[So] Source:J Struct Biol;202(1):82-93, 2018 Apr.
[Is] ISSN:1095-8657
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Cystathionine ß-synthase (CBS), the key enzyme in the transsulfuration pathway, links methionine metabolism to the biosynthesis of cellular redox controlling molecules. CBS catalyzes the pyridoxal-5'-phosphate-dependent condensation of serine and homocysteine to form cystathionine, which is subsequently converted into cysteine. Besides maintaining cellular sulfur amino acid homeostasis, CBS also catalyzes multiple hydrogen sulfide-generating reactions using cysteine and homocysteine as substrates. In mammals, CBS is activated by S-adenosylmethionine (AdoMet), where it can adopt two different conformations (basal and activated), but exists as a unique highly active species in fruit fly Drosophila melanogaster. Here we present the crystal structure of CBS from honeybey Apis mellifera, which shows a constitutively active dimeric species and let explain why the enzyme is not allosterically regulated by AdoMet. In addition, comparison of available CBS structures unveils a substrate-induced closure of the catalytic cavity, which in humans is affected by the AdoMet-dependent regulation and likely impaired by the homocystinuria causing mutation T191M.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180304
[Lr] Last revision date:180304
[St] Status:In-Data-Review

  5 / 2075 MEDLINE  
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[PMID]: 29175875
[Au] Autor:Quintas S; Dotor-García Soto J; Alonso-Cerezo MC; Carreras MT
[Ad] Address:Department of Neurology, Hospital Universitario de la Princesa, Madrid, Spain.
[Ti] Title:Late diagnosis of homocystinuria in an adult after extensive cerebral venous thrombosis.
[So] Source:Pract Neurol;18(1):49-51, 2018 Feb.
[Is] ISSN:1474-7766
[Cp] Country of publication:England
[La] Language:eng
[Pt] Publication type:EDITORIAL
[Em] Entry month:1711
[Cu] Class update date: 180223
[Lr] Last revision date:180223
[St] Status:In-Process
[do] DOI:10.1136/practneurol-2017-001795

  6 / 2075 MEDLINE  
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[PMID]: 29463473
[Au] Autor:Johnson M; Murphy E; Raheem A; Ralph D
[Ad] Address:Andrology Department, University College London Hospital, London, UK. Electronic address: markjohnson@doctors.org.uk.
[Ti] Title:Poorly Controlled Homocystinuria: A Rare Cause of Ischemic Priapism?
[So] Source:Sex Med;, 2018 Feb 17.
[Is] ISSN:2050-1161
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:We report on the 1st case of ischemic priapism secondary to poorly controlled homocystinuria. Homocystinuria is a rare, autosomal recessive, inherited disorder of metabolism that is caused by a deficiency of cystathionine synthase, leading to marked hyperhomocysteinemia. Arterial and/or venous thromboemboli are a major cause of mortality and morbidity in patients with homocystinuria. Untreated patients have a 50% chance of having a vascular event by 30 years of age. Increased homocysteine levels have been reported to upregulate prothrombotic factors and downregulate antithrombotic factors; in particular, increased homocystinuria has been found to downregulate nitric oxide (NO). Mice that are deficient in NO synthase in the cavernosal smooth muscles have a higher incidence of priapism. Decrease in NO synthase causes downregulation of cyclic guanosine monophosphate, phosphodiesterase type 5A, and Rho A/Rho-kinase. Because persistently increased homocysteine also downregulates NO, a similar mechanism could be proposed for priapism secondary to homocystinuria. In patients presenting with priapism, specific features of homocystinuria should be sought; in selected patients, screening with plasma total homocysteine might be appropriate. Ischemic priapism secondary to homocystinuria appears to respond well to the standard treatment options of aspiration, intracavernosal injection with phenylephrine, and, if required, a shunting procedure. Johnson M, Murphy E, Raheem A, Ralph D. Poorly Controlled Homocystinuria: A Rare Cause of Ischemic Priapism? Sex Med 2018;X:XXX-XXX.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180221
[Lr] Last revision date:180221
[St] Status:Publisher

  7 / 2075 MEDLINE  
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[PMID]: 28465033
[Au] Autor:Kim JI; Noh JY; Kim M; Park JM; Song HW; Kang MJ; Pyun JC
[Ad] Address:Department of Materials Sciences and Engineering, Yonsei University, Seoul, South Korea.
[Ti] Title:Newborn screening by matrix-assisted laser desorption/ionization mass spectrometry based on parylene-matrix chip.
[So] Source:Anal Biochem;530:31-39, 2017 08 01.
[Is] ISSN:1096-0309
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Newborn screening for diagnosis of phenylketonuria, homocystinuria, and maple syrup urine disease have been conducted by analyzing the concentration of target amino acids using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS) based on parylene-matrix chip. Parylene-matrix chip was applied to MALDI-ToF MS analysis reducing the matrix peaks significantly at low mass-to-charge ratio range (m/z < 500). Reproducibility of inter-spot and intra-spot analyses of amino acids was less than 10%. Methanol extraction was adopted for simple and rapid sample preparation of serum before mass spectrometric analysis showing 13.3 to 45% of extraction efficiency. Calibration curves for diagnosis of neonatal metabolic disorders were obtained by analyzing methanol-extracted serum spiked with target amino acids using MALDI-ToF MS. They showed good linearity (R > 0.98) and the LODs were ranging from 9.0 to 22.9 µg/mL. Effect of proteins in serum was estimated by comparing MALDI-ToF mass spectra of amino acids-spiked serum before and after the methanol extraction. Interference of other amino acids on analysis of target analyte was determined to be insignificant. From these results, MALDI-ToF MS based on parylene-matrix chip could be applicable to medical diagnosis of neonatal metabolic disorders.
[Mh] MeSH terms primary: Amino Acids/blood
Neonatal Screening/methods
Polymers/chemistry
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
Xylenes/chemistry
[Mh] MeSH terms secundary: Amino Acids/chemistry
Humans
Infant, Newborn
Limit of Detection
Reproducibility of Results
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Amino Acids); 0 (Polymers); 0 (Xylenes); 25722-33-2 (parylene)
[Em] Entry month:1708
[Cu] Class update date: 180207
[Lr] Last revision date:180207
[Js] Journal subset:IM
[Da] Date of entry for processing:170504
[St] Status:MEDLINE

  8 / 2075 MEDLINE  
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[PMID]: 29352562
[Au] Autor:Poloni S; Sperb-Ludwig F; Borsatto T; Weber Hoss G; Doriqui MJR; Embiruçu EK; Boa-Sorte N; Marques C; Kim CA; Fischinger Moura de Souza C; Rocha H; Ribeiro M; Steiner CE; Moreno CA; Bernardi P; Valadares E; Artigalas O; Carvalho G; Wanderley HYC; Kugele J; Walter M; Gallego-Villar L; Blom HJ; Schwartz IVD
[Ad] Address:Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
[Ti] Title:CBS mutations are good predictors for B6-responsiveness: A study based on the analysis of 35 Brazilian Classical Homocystinuria patients.
[So] Source:Mol Genet Genomic Med;, 2018 Jan 20.
[Is] ISSN:2324-9269
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine ß-synthase (CßS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. METHODS: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon-intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT-PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site-directed mutagenesis. RESULTS: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty-one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli-expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT-PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. CONCLUSIONS: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype-phenotype relationship was observed within families and for the four most common mutations.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180120
[Lr] Last revision date:180120
[St] Status:Publisher
[do] DOI:10.1002/mgg3.342

  9 / 2075 MEDLINE  
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[PMID]: 29294253
[Au] Autor:Navarro D; Azevedo A; Sequeira S; Ferreira AC; Carvalho F; Fidalgo T; Vilarinho L; Santos MC; Calado J; Nolasco F
[Ad] Address:Nephrology Department, Centro Hospitalar de Lisboa Central E.P.E., Hospital Curry Cabral, Rua da Beneficência 8, 1069-166, Lisbon, Portugal. Davidbnavarro@gmail.com.
[Ti] Title:Atypical adult-onset methylmalonic acidemia and homocystinuria presenting as hemolytic uremic syndrome.
[So] Source:CEN Case Rep;, 2018 Jan 02.
[Is] ISSN:2192-4449
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Thrombotic microangiopathy (TMA) syndromes can be secondary to a multitude of different diseases. Most can be identified with a systematic approach and, when excluded, TMA is generally attributed to a dysregulation in the activity of the complement alternative pathways-atypical hemolytic uremic syndrome (aHUS). We present a challenging case of a 19-year-old woman who presented with thrombotic microangiopathy, which was found to be caused by methylmalonic acidemia and homocystinuria, a rare vitamin B12 metabolism deficiency. To our knowledge, this is the first time that an adult-onset methylmalonic acidemia and homocystinuria presents as TMA preceding CNS involvement.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180102
[Lr] Last revision date:180102
[St] Status:Publisher
[do] DOI:10.1007/s13730-017-0298-6

  10 / 2075 MEDLINE  
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[PMID]: 27778219
[Au] Autor:Morris AA; Kozich V; Santra S; Andria G; Ben-Omran TI; Chakrapani AB; Crushell E; Henderson MJ; Hochuli M; Huemer M; Janssen MC; Maillot F; Mayne PD; McNulty J; Morrison TM; Ogier H; O'Sullivan S; Pavlíková M; de Almeida IT; Terry A; Yap S; Blom HJ; Chapman KA
[Ad] Address:Institute of Human Development, University of Manchester, Manchester, UK. Andrew.morris@cmft.nhs.uk.
[Ti] Title:Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.
[So] Source:J Inherit Metab Dis;40(1):49-74, 2017 Jan.
[Is] ISSN:1573-2665
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 µmol/L. Nevertheless, we recommend keeping the concentration below 100 µmol/L because levels fluctuate and the complications associated with high levels are so serious.
[Mh] MeSH terms primary: Cystathionine beta-Synthase/deficiency
Homocystinuria/diet therapy
Homocystinuria/drug therapy
[Mh] MeSH terms secundary: Betaine/metabolism
Homocysteine/metabolism
Humans
Methionine/metabolism
Pyridoxine/therapeutic use
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0LVT1QZ0BA (Homocysteine); 3SCV180C9W (Betaine); AE28F7PNPL (Methionine); EC 4.2.1.22 (Cystathionine beta-Synthase); KV2JZ1BI6Z (Pyridoxine)
[Em] Entry month:1712
[Cu] Class update date: 171204
[Lr] Last revision date:171204
[Js] Journal subset:IM
[Da] Date of entry for processing:161026
[St] Status:MEDLINE
[do] DOI:10.1007/s10545-016-9979-0


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