Cobalamine, congenital deficiency
(Congenital deficiency in vitamin B12, Gräsbeck-Imerslund disease)
Infant: pallor, lethargy, developmental delay. Later: hypotonia, athetotic movements. Child and untreated adult: megaloblastic anemia and neurological signs of vitamin B12 deficiency (Biermer disease) (see this term): neurologic disorder, cutaneous hyperpigmentation on the joints, vitiligo, glossitis, angular stomatitis, linear stripes on the fingernails.
Congenital deficiency of cobalamin may be the result of:
- combined adenosyl - and methyl-cobalamin deficiency: all patients presnt with methylmalonic aciduria and homocystinuria
* cobalamin F (cbl F): mutation of the LMBRD1 gene (6q13); disorder of the transport of cobalamine through the lysosomial membrane; first signs during the 1st year: developmental delay, megaloblastic anemia or pancytopenia, stomatitis
* cobalamin C (Cbl C) [MIM 277 400]: the most frequent (1/100,000). Mutation of the MMACHC gene (1p23.2); signs (acute) in the 1st month or the 1st year: lethargy, feeding problems, pancytopenia, abnormal movements, convulsions, retinopathy; in addition to methylmalonic aciduria and homocystinuria, it leads sometimes to an atypical hemolytic uremic syndrome (see these terms). Some forms with later onset (10 %) have been reported: psychiatric problems, progressive encephalopathy, convulsions
* cobalamin D (cbl D): very rare; mutation of the MMADHC gene (2q32); it results in methylmalonic aciduria or homocystinuria (see these terms)
- adenosylcobalamin deficiency: mutation of the MMAA gene (4q31.1-q31.2) (cbl A form) or mutation of the MMAB gene (12q24) (clb B form) causing methylmalonic aciduria (see this term) similar to the phenotype secondary to methylmalonyl-CoA deficiency. Treatment: protein restriction and vitamin B12 supplementation
- methylcobalamin deficiency: extremely rare; mutation of the MTRR gene (5p15.2-15.3) (clb E form) or mutation of the MTR gene (1q43) (cbl G form) [MIM 250 940]; first signs in the 1st year: megaloblastic anemia and neurologic disorders (developmental delay, hypo - or hypertonia, ataxia, seizures, homocystinuria) and important risk of thrombotic microangiopathy with renal failure; the signs of the cbl G form appear later. Treatment: vitamin B12 and betaine
Some acquired forms of deficiency in vitamin B12 are due to:
- either an acquired deficiency in intrinsic factor caused by an autoimmune disease involving the gastric parietal cells and the intrinsic factor (pernicious anemia), often associated with other immunological diseases (vitiligo, thyroiditis, diabetes),
- either one of the causes leading to vitamin B12 deficiency (see this term)
absolute contraindication to the use of the N2O; check complete blood count; management according to the neurological situation; in case of restricted protein intake, ensure a short fasting period and an adequate supply of glucose to avoid an increased catabolism.
- Felmet K, Robins B, Tilford D, Hayflick SJ.
Acute neurologic decompensation in an infant with cobalamin deficiency exposed to nitrous oxide.
J Pediatr 2000; 137: 427-8.
- Watkins D, Rosenblatt DS, Fowler B.
Disorders of cobalamin and folate transport and metabolism.
In Inborn metabolic diseases, 5th edition by Saudubray, van den Berghe & Walter, Springer 2012, p 386-402.
- Rahmandar MH, Bawcom A, Romano ME, Hamid R.
Cobalamin C deficiency of an adolescent with altered mental status and anorexia.
Pediatrics 2014; 134: e1709-17
- Krueger JM, Piantino J, Smith GM et al.
A treatable metabolic cause of encephalopathy: cobalamin C deficiency of a 8-year-old male.
Pediatrics 2015; 135; e202-7.
- Mullikin D, Pillai N, Sanchez R, O’Donnell-Luria AH, Kritzer A et al.
Megaloblastic anemia progressing to severe thrombotic microangiopathy in patients with disordered vitamin B12 metabolism : case reports and literature review .
J Pediatr 2018; 202: 315-9.
Updated: January 2019