title: Should transcobalamin deficiency be treated aggressively?
abstract: Transcobalamin (transcobalamin II, TC) transports plasma vitamin B(12) (cobalamin, Cbl) into cells. TC deficiency is a rare autosomal recessive disorder causing intracellular Cbl depletion, which in turn causes megaloblastic bone marrow failure, accumulation of homocysteine and methylmalonic acid, and methionine depletion. The clinical presentation reflects intracellular Cbl defects, with early-onset failure to thrive with gastrointestinal symptoms, pancytopenia, and megaloblastic anemia, sometimes followed by neurological complications. We report the clinical, biological, and molecular findings and the outcome in five TC-deficient patients. The three treated early had an initial favorable outcome, whereas the two treated inadequately had late-onset severe neuro-ophthalmological impairment. Even if the natural course of the disease over time might also result in late-onset symptoms in the aggressively treated patients, these data emphasize that TC deficiency is a severe disorder requiring early detection and probably long-term aggressive therapy. Mutation analysis revealed six unreported mutations in the TCN2 gene. In silico structural analysis showed that these mutations disrupt the Cbl-TC interaction domain and/or the putative transcobalamin-transcobalamin receptor interaction domain.
authors.affiliation: Service de Neuropédiatrie & Maladies Métaboliques, Centre de référence Maladies Métaboliques, CHU Robert Debré, APHP, Paris, France. manuel.schiff@rdb.aphp.fr
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier de Baulny
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Bard
authors.forename: Vincent
authors.initials: V
authors.lastname: Barlogis
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Moat
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Graham
authors.initials: G
authors.lastname: Shortland
authors.forename: Guy
authors.initials: G
authors.lastname: Touati
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
mesh_terms: D000749:Anemia, Megaloblastic / Q000628:therapy; D001692:Biological Transport; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006710:Homocysteine / Q000737:chemistry; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008715:Methionine / Q000378:metabolism; D008764:Methylmalonic Acid / Q000378:metabolism; D009154:Mutation; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D014155:Transcobalamins / Q000172:deficiency* / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D014155:Transcobalamins; D006710:Homocysteine; D008764:Methylmalonic Acid; D008715:Methionine