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

Abstract

ObjectivesTranscobalamin 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 presentation4-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.ConclusionsIn 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.

Long-term Outcome of a Patient With Transcobalamin Deficiency Caused by the Homozygous c.1115_1116delCA Mutation in TCN2 Gene: a Case Report

“…Our hypothesis was con rmed genetically only at the age of 29 years of age when we found a c.115_116delCA homozigous mutation in TCN2 gene, further con rmed by the parents'genetic analysis that showed the same mutation in the heterozygous status. About 50 cases have been reported in the literature of TCN2 variants (20), our mutation c.115_116delCA in exon 8 was cited among these, indeed it was reported in only one patient in which this mutation was present in association with c.501_503delCCA in exon 4. In silico analysis demonstrate that exon 8 is the region involved in cobalamin binding site, whereas mutation in exon 4 should affect TC-TC receptor interaction (15).…”

“…Twenty-ve pathogenic mutations in TCN2 gene have been identi ed (10). Nonsense mutations and point mutations that activate exonic cryptic splice sites have also been reported (12,13), as well as, polymorphic variants have also been described (8,13).…”

A novel TCN2 mutation with unusual clinical manifestations of hemolytic crisis and unexplained metabolic acidosis: expanding the genotype and phenotype of transcobalamin II deficiency

“…Later, when transcobalamin defect and its associated increased homocysteine level was suspected, plasma homocysteine level was measured using a separate specific test. Less than 60 patients and 50 TCN2 variants have been reported worldwide in which many cases were reported from regions with a high rate of consanguinity, including Turkey [1,2,[11][12][13][14]. To our knowledge, the present patient is the first case report from a Southeast Asian country with a novel TCN2 variant, c.428-2A > G. The variant was subsequently submitted to ClinVar database and now is accessible using a number SCV001981507 (https:// www.…”

“…A case report of a TC deficiency patient who exhibited urinary methylmalonic acid excretion at birth may indicate intrauterine onset of the metabolic derangement and neurologic damage of this intriguing disorder [18]. This may explain neurocognitive impairment in some patients despite receiving prompt diagnosis and treatment at birth [14].…”

Case report: Novel compound-heterozygous mutations in the TCN2 gene identified in a chinese girl with transcobalamin deficiency

“…The aberrant expression of TCN2 gene is a mechanism contributing to the pathogenesis of TC deficiency. Currently, about 60 cases of TC deficiency have been reported worldwide (Trakadis et al, 2014;Kose et al, 2020), with only one case from China (Zhan et al, 2020). A total of 48 variants in TCN2 gene have been reported in HGMD to date, including 38 diseasecausing mutations (Figure 2).…”