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To date, more than 40 cases of TC have been described in the literature.

TC typically manifests in the first few months of life. Patients present with one or more of the following signs: weight loss, failure to thrive, diarrhea, vomiting, lethargy, irritability, pallor, ulcers of oral mucous membranes and impaired development. Myoclonus, decreased reflexes in the lower extremities and toe-walking may be observed. Severe infections (i.e. Pneumocystis carinii, pneumococcal meningitis, Escherichia coli, urinary tract infection, Salmonella sepsis, aseptic meningitis and gastro-enteritis) in the first year of life are also reported. In rare cases, the disease may be asymptomatic. Metabolic stroke and peripheral neuropathy have been observed in one case.

TC is caused by mutations in the TCN2 gene (22q12.2) which encodes transcobalamin, a transporter of cobalamin (vitamin B12). Cobalamin has an important role in the metabolism of both homocysteine and methylmalonic acid as a cofactor for methionine synthase and methylmalonyl-CoA mutase, respectively. Methionine synthase helps to maintain levels of methionine and its derivative, S-adenosylmethionine, which is required for neurotransmitter synthesis and methylation of DNA, RNA, lipids and proteins. It also prevents accumulation of homocysteine.

Diagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid.

Differential diagnosis includes inherited disorders of intestinal cobalamin absorption (Gräsbeck-Imerslund disease and congenital intrinsic factor deficiency); inborn errors of cellular cobalamin metabolism, in particular the forms resulting in combined homocystinuria and methylmalonic aciduria (cblC, cblD, cblF, cblJ and cblX); and pernicious anemia (see these terms).

Prenatal diagnosis is based on genetic screening of TCN2 or incubation of amniocytes in medium lacking any exogenous source of transcobalamin supplemented with radiolabeled cobalamin followed by measurement of transcobalamin-bound cobalamin.

Transmission is autosomal recessive.

Treatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended.

TC is a severe, life-threatening and rapidly progressing disease. Treatment, started early, is highly effective and reverses the clinical and hematological manifestations of the disease. If left untreated, immunologic deficiency (marked hypogammaglobulinemia with absence of specific antibody production after antigenic stimulation) and neurological problems (severe intellectual disabilities, ataxia, and pyramidal deficit) can develop.