The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis.
Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.
Metabolic Unit, University Children's Hospital, Römergasse 8, CH-4058 Basel, Switzerland.
Terttu
T
Suormala
Matthias R
MR
Baumgartner
David
D
Coelho
Petra
P
Zavadakova
Viktor
V
Kozich
Hans Georg
HG
Koch
Martin
M
Berghaüser
James E
JE
Wraith
Alberto
A
Burlina
Adrian
A
Sewell
Jürgen
J
Herwig
Brian
B
Fowler
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000378:metabolism; D000293:Adolescent; D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003038:Cobamides / Q000096:biosynthesis / Q000172:deficiency*; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005816:Genetic Complementation Test; D006710:Homocysteine / Q000737:chemistry; D006712:Homocystinuria / Q000235:genetics; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008765:Methylmalonyl-CoA Mutase / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D014805:Vitamin B 12 / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000235:genetics*
D003038:Cobamides; D018076:DNA, Complementary; D006710:Homocysteine; D008715:Methionine; C019476:mecobalamin; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide; D014805:Vitamin B 12