Objectives Transcobalamin II (TC) is an essential plasma protein for the absorption, transportation, and cellular uptake of cobalamin. TC deficiency presents in the first year of life with failure to thrive, hypotonia, lethargy, diarrhea, pallor, mucosal ulceration, anemia, pancytopenia, and agammaglobulinemia. Herein, we present TC deficiency diagnosed in two cases (twin siblings) with a novel variant in the TCN2 gene. Case presentation 4-month-old twins were admitted with fever, respiratory distress, vomiting, diarrhea, and failure to thrive. Physical examination findings revealed developmental delay and hypotonia with no head control, and laboratory findings were severe anemia, neutropenia, and hypogammaglobulinemia. Despite normal vitamin B12 and folate levels, homocysteine and urine methylmalonic acid levels were elevated in both patients. Bone marrow examinations revealed hypocellular bone marrow in both cases. The patients had novel pathogenic homozygous c.241C>T (p.Gln81Ter) variant in the TCN2 gene. In both cases, with intramuscular hydroxycobalamin therapy, laboratory parameters improved, and a successful clinical response was achieved. Conclusions In infants with pancytopenia, growth retardation, gastrointestinal manifestations, and immunodeficiency, the inborn error of cobalamin metabolism should be kept in mind. Early diagnosis and treatment are crucial for better clinical outcomes. What is new? In literature, to date, less than 50 cases with TC deficiency were identified. In this report, we presented twins with TCN2 gene mutation. Both patients emphasized that early and aggressive treatment is crucial for achieving optimal outcomes. In this report, we identified a novel variation in TCN2 gene.

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Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature

Transcobalamin (TC) transports vitamin B12 from blood into cells. TC II deficiency is a rare autosomal recessive disorder. It is characterized by failure to thrive, diarrhoea, pallor, anaemia, pancytopenia or agammaglobulinemia. It is usually confirmed by molecular analysis of the TCN2 gene. We report a 2-month-old girl with two novel mutations, which were first reported in humans. We present a 2-month-old Chinese girl with pancytopenia, severe combined immunodeficiency disease, and megaloblastic anaemia. Targeted next-generation sequencing (NGS) was performed, which detected compound heterozygous variants in exon 7 of the TCN2 gene (Mutation 1: c.1033 C > T; Mutation 2: c.1017-1031delinsGTAACAGAGATGGTT). These mutations result in stop codons in TCN2. The c.1033C > T mutation causes a stop at codon 345 (p.Gln345Ter), and the c.1017-1031delinsGTAACAGAGATGGTT mutation causes a stop at codon 340 (p.Leu340Ter). After being diagnosed, she was treated with intramuscular 1 mg hydroxycobalamin (OH-Cbl) every day for 2 months. The CBC value returned to normal after half a month. The peripheral blood lymphocyte subsets and immunoglobulin recovered after 2 months. Then, the dosage of OH-Cbl was gradually reduced. TC II deficiency is a serious complication that requires lifelong treatment. Its diagnosis is difficult due to the lack of clearly identifiable symptoms. Genetic testing should be performed as early as possible if this disease is suspected. The specific observations of this case report make a considerable contribution to the literature and provide a reference for the diagnosis and treatment of future cases.

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Identification of transcobalamin deficiency with two novel mutations in the TCN2 gene in a Chinese girl with abnormal immunity: a case report.

BACKGROUND Osteoporosis (OP) is a systemic bone disease characterized by decreased bone mass, destruction of the bone tissue microstructure, increased bone brittleness and an increased risk of fracture. OP has a high incidence rate and long disease course and is associated with serious complications. Yigu decoction (YGD) is a compound prescription in traditional Chinese medicine that is used to treat OP. However, its mechanism in OP is not clear. This study used a tandem mass tag (TMT)quantitative proteomics method to explore the potential bone-protective mechanism of YGD in an osteoporotic rat model. MATERIALS AND METHODS A rat model of OP was established by ovariectomy. Eighteen 12-week-old specific-pathogen-free female Wistar rats weighing 220 ± 10 g were selected. The eighteen rats were randomly divided into 3 groups (n = 6 in each group): the normal, model and YGD groups. The right femurs from each group were subjected to quantitative biological analysis. TMT quantitative proteomics was used to analyze the proteins extracted from the bone tissue of rats in the model and YGD groups, and the differentially expressed proteins after intervention with YGD were identified as biologically relevant proteins of interest. Functional annotation correlation analysis was also performed to explore the biological function and mechanism of YGD. RESULT Compared with the model group, the YGD group showed significant upregulation of 26 proteins (FC > 1.2, P < 0.05) and significant downregulation of 39 proteins (FC < 0.833, P < 0.05). Four important targets involved in OP and 5 important signaling pathways involved in bone metabolism were identified. CONCLUSIONS YGD can significantly increase the bone mineral density (BMD) of osteoporotic rats and may play a therapeutic role by regulating target proteins involved in multiple signaling pathways. Therefore, these results improve the understanding of the OP mechanism and provide an experimental basis for the clinical application of YGD in OP treatment.

/pdf/quantitative-proteomics-reveals-the-effect-of-yigu-decoction-3s8upgletl.pdf

Quantitative proteomics reveals the effect of Yigu decoction (YGD) on protein expression in bone tissue

A single-center cross-sectional study on the clinical profile of pancytopenia and a novel scoring system for megaloblastic anemia

Transcobalamin (TC) transports cobalamin (vitamin B12) from plasma into cells. Its congenital deficiency is a rare autosomal recessive disorder due to mutations in the TCN2 gene. It causes intracellular cobalamin depletion with early onset in the first months of life, failure to thrive with pallor due to megaloblastic anemia. It can be associated with pancytopenia, gastrointestinal symptoms with vomiting, diarrhea, and neurological complications with myelopathy. Aggressive vitamin B12 parenteral therapy must be instituted early and continuously. Retinopathy and maculopathy are rarely associated with this condition. We report the electrophysiological results of one TC-deficient patient diagnosed at the age of 4 months immediately and continuosly treated by hydroxocobalamin IM. Her visual function was followed by eight ophthalmological assessments, eight flash-ERG, six EOG, one mf-ERG, and seven P-ERG recordings over a 10-year period, between the age of 2y 9 m and 12y 6 m. Her ophthalmological assessment including visual acuity, fundi, optical coherent tomography (OCT), and retinal nerve fiber layer (RNFL) remained normal. From the age of 2y 9 m to 5y, dark-adapted and light-adapted flash-ERGs, EOGs and pattern-ERG were normal. From the age of 6y 4 m to 12y 6 m, dark-adapted flash-ERGs and EOGs remained normal. Cone a-wave amplitudes remained normal, whereas cone b-wave and flicker-response amplitudes were decreased. At the age of 12y 6 m, mf-ERG N1P1 amplitudes on the central 30° were decreased. From the age of 7y 4 m to 12y 6 m, P-ERG P50 amplitudes were decreased with no N95. While clinical and anatomical assessments remained normal over a 10-year period, patient’s electrophysiological results suggested the progressive onset of a subclinical retinopathy of inner-cone dystrophy type, and a subclinical maculopathy on the central 30° including the ganglion cell layer deficiency on the central 15°, despite continuous intramuscular treatment, RPE and scotopic system remaining normal. The origins of such subclinical retinopathy and maculopathy are unknown and independent of early disease identification and aggressive intramuscular hydroxocobalamin therapy.

Subclinical maculopathy and retinopathy in transcobalamin deficiency: a 10-year follow-up.

Transcobalamin (TC) deficiency is a rare autosomal recessive inborn error of cobalamin transport which clinically manifests in early infancy. We describe a child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B12 metabolism except normal serum B12 levels. He was started on empirical parenteral cobalamin supplements at 2 months of age; however, the definitive diagnosis could only be established at 6 years of age when a genetic evaluation revealed homozygous nonsense variation in exon 8 of the TCN2 gene (chr22:g.31019043C>T).

https://casereports.bmj.com/content/bmjcr/12/10/e232319.full.pdf

Saroj Kumar Patnaik

Papers

Transcobalamin deficiency: vitamin B12 deficiency with normal serum B12 levels.