Long-term Outcome of 4 Patients With Transcobalamin Deficiency Caused by 2 Novel TCN2 Mutations

Abstract

Cobalamin (vitamin B12 [Cbl]) is an essential cofactor for many biochemical pathways. Transcobalamin (TC) is required to internalize Cbl into the cells through membrane receptor-mediated endocytosis. Cbl is then processed in the cytoplasm and mitochondria by complementation factors leading to its active metabolites; methylcobalamin and 5-deoxyadenosyl-cobalamin. Deficiency of TC results in an elevation in methylmalonic acid and homocysteine. Patients usually present with macrocytic anemia, pancytopenia, failure to thrive, gastrointestinal symptoms, and neurological dysfunction. In this study, we report 4 patients from 2 unrelated families, with confirmed diagnosis of TC deficiency. Patients initially had a typical presentation of TC deficiency: severe diarrhea and vomiting, recurrent infections, stomatitis, macrocytic anemia, and neutropenia. Interestingly one of the patients was diagnosed at 3 months of age and developed ataxic gait related to cerebellar atrophy at the age of 14 months. His elder affected sibling was diagnosed at 5 months of age was completely normal. Two sibs, diagnosed at 2 months of age and immediately after birth, had autism spectrum disorder. Molecular investigations showed 2 novel mutations in TCN2 gene. Patients were treated and stayed stable on weekly injection of Cbl. In conclusion, TC deficiency has a wide heterogeneity in clinical phenotype, genotype, laboratory, and radiologic findings. Early detection of the disease and early initiation of aggressive parenteral treatment is probably associated with better prognosis and disease control.

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…Immunological abnormalities (agammaglobulinemia, recurrent infections, low T‐cell, B‐cell, or IgG counts), glossitis and skin rashes were noticed in a minority of patients. Mild brain atrophy and delayed myelination have also been observed.…”

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

“…Furthermore, Nashabat et al reported successful clinical outcome in two TC deficiency diagnosed patients with 1 mg i.m. weekly methylcobalamin (methyl-Cbl) [18]. Folic acid and betaine administrations were also reported in TC deficiency [6] (Table 2).…”

“…No genotype-phenotype correlation was reported in TC deficiency. Previously, insertions, deletions, splice-site, and nonsense mutations were reported [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (Table 2). In our patients, we revealed a novel nonsense premature stop codon variation in exon two of the TCN2 gene.…”

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

“… Namour et al 2003 [ 7 ] 1 c.64 + 4A > T p.? Nashabat et al 2017 [ 14 ] 7 c.1106 + 1G > A p.Met315fs Nissen et al 2010 [ 15 ] 8 deletion ex. 8 p.?…”