SUMMARY

 

1.  Transcobalamin II deficiency is an autosomal recessive disease with initial presentation during infancy.  It is characterized by the following clinical features: 

 

-Megaloblastic anemia
-Neutropenia
-Thrombocytopenia
-Neurologic abnormalities (developmental delay, gait disturbance, weakness, epilepsy)
-Failure to thrive
-Diarrhea and vomiting
-Severe infections due to immunodeficiency

 

2.  Specific immune abnormalities include hypogammaglobulinemia, specific antibody deficiency and neutropenia.  Patients suffer from both bacterial and viral infections.

 

3.  Transcobalamin II is a transport protein for vitamin B12 and facilitates its cellular uptake by receptor mediated endocytosis. A deficiency of Transcobalamin II results in a lack of vitamin B12 entry into cells.

 

4.  The majority of vitamin B12 in circulation is found bound to haptocorrin (which cannot be taken up by cells) rather than transcobalamin.  As a result, circulating vitamin B12 levels may be normal in patients. 

 

5.  The diagnosis is suspected by the presence of classic clinical and laboratory features.  Patients also have combined methylmalonic aciduria and homocystinuria. TCN2 gene sequencing is currently available.  

 

6.  The clinical and immunologic abnormalities resolve after supplementation with high doses of oral or intramuscular hydroxycobalamin.  However, if there is a significant delay in treatment, the neurologic abnormalities may become irreversible.    

 

 

 

 

OVERVIEW

 

     Transcobalamin II deficiency is an autosomal recessive disease with initial presentation during infancy.  It is characterized by the following clinical features:

 

-Megaloblastic anemia
-Neutropenia
-Thrombocytopenia
-Neurologic abnormalities (developmental delay, gait disturbance, weakness, epilepsy)
-Failure to thrive
-Diarrhea and vomiting
-Severe infections due to immunodeficiency

 

     Specific immune abnormalities include hypogammaglobulinemia, specific antibody deficiency and neutropenia.  Patients suffer from both bacterial and viral infections.

 

     Transcobalamin II is a transport protein for vitamin B12 and facilitates its cellular uptake by receptor mediated endocytosis. A deficiency of Transcobalamin II results in a lack of vitamin B12 entry into cells.

 

     The majority of vitamin B12 in circulation is found bound to haptocorrin (which cannot be taken up by cells) rather than transcobalamin.  As a result, circulating vitamin B12 levels may be normal in patients. 

 

 

 

EVALUATION

 

The diagnosis is suggested by the presence of megaloblastic anemia, neurologic abnormalities, FTT, diarrhea, vomiting, and recurrent infections.  

 

Step 1:  Immune Evaluation

 

-CBC with Differential
-IgG, IgM, IgA
-Specific antibody responses to vaccine antigens

 

-The CBC may demonstrate pancytopenia including megaloblastic anemia, neutropenia, leukopenia, and thrombocytopenia. 

-Low IgG levels have been reported in patients. 

-Responses to both protein antigens (tetanus and diphtheria) as well as polysaccharide antigens (pneumovax) should be evaluated.  Impaired specific vaccine responses have been reported in patients.

 


Step 2:  Diagnosis of Transcobalamin II deficiency


-Serum cobalamin (B12) levels
-Urine methylmalonic acid and homocysteine levels
-TCN2 gene sequencing

 

-Patients typically have normal serum cobalamin levels (circulating cobalamin is bound to haptocorrin, not transcobalamin II).

-Patients have both methlmalonic aciduria and homocysteinuria.

-TCN2 gene sequencing is commercially available. 

 

 

 

 

MANAGEMENT

 

     The clinical and immunologic abnormalities resolve after supplementation with high doses of oral or intramuscular hydroxycobalamin.  However, if there is a significant delay in treatment, the neurologic abnormalities may become irreversible.   

 

 

 

 

RESOURCES

 

Diagnostic Resources    

 

1.BAYLOR - TCN2 gene sequencing