Abstract
Objectives
Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected.
Case presentation
Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment.
Conclusions
This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving.
Learning points
The symptoms associated with hypovitaminosis B12 are heterogeneous; the combination of pancytopenia, gastrointestinal involvement, growth retardation, and immunodeficiency can alert the medical community for an early diagnosis of TC deficiency.
Do not be guided by isolated vitamin B12 values as a marker of vitamin deficiency, take into account functional biomarkers, mainly methylmalonic acid.
TC deficiency may be identifiable though NBS.
What is new?
This manuscript describes the clinical and biochemical data, molecular diagnosis, and long-term treatment of patients with TC deficiency in a Metabolic Center of a high-complexity hospital from the last 10 years.
This report represents the first characterization of TC deficiency in pediatric Argentinean patients. Mutation analysis revealed one unreported mutation in the TCN2 gene.
This study contributes to a better understanding of TC deficiency, expanding upon the spectrum of TCN2 mutations, and supports the early diagnosis and proper treatment of similar cases in the future.
We analyzed C3 and C3/C2, which are sparsely reported on the literature. NBS could reveal more undiagnosed cases.
Acknowledgments
The authors would like to thank the multidisciplinary team at the Inborn Errors of Metabolism, Hematology and inmmunology in Garrahan Hospital with the diagnosis and assistance of the patients.
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Research ethics: The local Institutional Review Board deemed the study exempt from review” if the IRB specifically exempted the study from review.
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Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
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Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission. Dr Bindi: Involved in data collection. Involved in design of the project and analysis and interpretation of the data. Drafting the article and critical revision. Dr Eiroa: Critical revision of the article and approved the final manuscript as submitted. Dr Crespo: Involved in analysis and data interpretation and drafting the molecular analysis. Dr Rossetti: Data collection and data interpretation. Dr Bouso: Data collection and data interpretation. Lic Tagliavini: Data collection and data interpretation. Dr Lochner: Data collection and data interpretation.
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Competing interests: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: The raw data can be obtained on request from the corresponding author.
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