Update on transcobalamin deficiency: clinical presentation, treatment and outcome

Abstract

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

False low holotranscobalamin levels in a patient with a novel TCN2 mutation

“…Indicated at the top of the curve is the void volume (V 0 ), the elution volumes for haptocorrin (V HC ), albumin (V alb ), transcobalamin (V TC ) ant the total volume (V t ). Haptocorrin (HC) and transcobalamin [13] were measured in the fractions by ELISA and are indicated in pmol/L. 57Co-Cbl was counted in the fractions and is indicated in counts per minute (CPM).…”

“…The condition leads to severe Cbl deficiency most often diagnosed within the first year of life [11,12], and is caused by mutations in the TCN2 gene. So far, small insertion/deletion variants (indels), large deletions and mutations leading to exon skipping have been identified in TC deficient patients [13]. Healthy individuals also harbor variations in the TCN2 gene.…”

Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario

“…Patients with GIF deficiency present with low serum cobalamin levels and megaloblastic anemia in comparison to TC and MMA deficiencies where B 12 levels are usually normal (Trakadis et al 2013). Other presentations include pancytopenia, splenomegaly, hepatomegaly, peripheral neuropathy, joint pain and swelling, anorexia, diarrhea, or infantile death Overgaard et al 2010).…”

“…(Prasad et al 2008;Trakadis et al 2013), methylmalonic aciduria (MMA; OMIM #251100, MMAA mutation) (Trakadis et al 2013), and intrinsic factor deficiency (IFD; OMIM #261000, GIF mutation) (Tanner et al 2005). Gastric intrinsic factor (GIF) is a cofactor produced by the parietal cells of the stomach.…”

“…The GIF-B 12 complex allows for endocytosis of B 12 by the mucosal cells of the distal ileum via a cubam receptor composed of two proteins, cubilin and amnionless (Watkins and Rosenblatt 2011). Serum vitamin B 12 is primarily transported by haptocorrin and transported into cells by transcobalamin (Trakadis et al 2013) (see Fig. 1).…”