Vitamin B 12-responsive methylmalonic aciduria due to a new inborn error of adenosylcobalamin synthesis, cblH

Abstract

Vitamin B12-responsive methylmalonic aciduria is characterized by deficient synthesis of adenosylcobalamin (AdoCbl) and decreased activity of the AdoCbl-dependent mitochondrial enzyme, methylmalonylCoA mutase. Two distinct disorders of AdoCbl synthesized have been characterized (cblA and cblB) and they can be distinguished on the basis of somatic cell complementation analysis. Such studies have clinical usefulness because in general cblA patients have a better prognosis than do cblB patients. We reported a patient whose fibroblasts had the clinical and biochemical features of the cblA class but complemented cells from all known inborn errors of cobalamin metabolism that cause methylmalonic aciduria, including cblA. The disorder in this patient was designated as cblA variant. Cells from this patient were tested against a panel of 29 cell lines from cblA patients and complemented all members of this panel. These studies strongly suggest that this patient represents a novel complementation class which we have called cblH. Detailed complementation analysis of a panel of 10 cblA lines provided evidence of interallelic complementation. The presence of this interallelic complementation indicates that care must be taken in the use of complementation analysis to identify cblA patients. These studies suggest that additional biochemical steps are required for the reduction and adenosylation of cobalamin. The full clinical spectrum of the new cblH class and its implications remains to be defined.