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      Homocystinuria due to cystathionine beta-synthase (CBS) deficiency in Russia: Molecular and clinical characterization

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          Abstract

          We present the results of the 45-year clinical observation of 27 Russian homocystinuria patients. We made a mutation analysis of the CBS gene for thirteen patients from eleven unrelated genealogies. All patients except for the two were compound heterozygotes for the mutations detected. The most frequent mutation in the cohort investigated was splice mutation IVS11-2a->c. We detected one new nonsense mutation, one new missense-mutation and three novel small deletions. We also report the clinical case of the B 6-responsive patient genotyped as Ile278Thr/Cys109Arg.

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          Most cited references 15

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          Cystathionine beta-synthase mutations in homocystinuria.

          The major cause of homocystinuria is mutation of the gene encoding the enzyme cystathionine beta-synthase (CBS). Deficiency of CBS activity results in elevated levels of homocysteine as well as methionine in plasma and urine and decreased levels of cystathionine and cysteine. Ninety-two different disease-associated mutations have been identified in the CBS gene in 310 examined homocystinuric alleles in more than a dozen laboratories around the world. Most of these mutations are missense, and the vast majority of these are private mutations. The two most frequently encountered of these mutations are the pyridoxine-responsive I278T and the pyridoxine-nonresponsive G307S. Mutations due to deaminations of methylcytosines represent 53% of all point substitutions in the coding region of the CBS gene.
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            A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency.

            We review the evidence that in Denmark and probably certain other European countries the number of individuals identified with homocystinuria due to homozygosity for the widespread c.833T>C (p.I278T) mutation in the gene that encodes cystathionine beta-synthase (CBS) falls far short of the number of such individuals expected on the basis of the heterozygote frequency for this mutation found by molecular screening. We conclude that the predominant portion of such homozygotes may be clinically unaffected, or may be ascertained for thromboembolic events occurring no sooner than the third decade of life. If so, there was significant ascertainment bias in the time-to-event curves previously published describing the natural history of untreated CBS deficiency Mudd et al. and these curves should be used with care.
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              Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders.

              Several inherited metabolic disorders have been associated with stroke particularly in newborns, children, and young adults. In part 1, we discussed the genetics, stroke pathophysiology, clinical presentation, diagnosis, and treatment of Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. In part 2, we overview homocystinuria, organic acidurias, and urea cycle disorders.
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                Author and article information

                Contributors
                Journal
                Mol Genet Metab Rep
                Mol Genet Metab Rep
                Molecular Genetics and Metabolism Reports
                Elsevier
                2214-4269
                27 December 2017
                March 2018
                27 December 2017
                : 14
                : 47-54
                Affiliations
                [a ]Research Centre for Medical Genetics, Moscow, Russia
                [b ]Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, Moscow, Russia
                Author notes
                Article
                S2214-4269(17)30116-7
                10.1016/j.ymgmr.2017.11.001
                5758839
                29326875
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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