The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis

Abstract

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.

Severe Neonatal Metabolic Decompensation in Methylmalonic Acidemia Caused by CblD Defect

“…Likewise, also this patient's family compliance had not been optimal. Of the three cblD-MMA patients that have been reported in the literature (Cooper et al 1990;Suormala et al 2004;Miousse et al 2009), none of them presented with an acute neonatal decompensation with severe hyperammonemia and coma comparable to what we have found in our patient. They presented with a late-onset condition, probably more consistent with a vitamin-responsive disorder.…”

“…Although propionate incorporation was completely normalized in vitro after the addition of OHCbl, it is possible that his in vivo responsiveness was only partial thereby promoting residual MMA production. In this regard, also the patient reported by Suormala et al (2004) was treated with protein restriction and still had a residual excretion of MMA. Likewise, also this patient's family compliance had not been optimal.…”

“…To the best of our knowledge only 18 cblD patients have been reported in the literature so far (6 cblD-MMA/HC, of whom two were brothers, 6 cblD-HC and 6 cblD-MMA) (Goodman et al 1970;Cooper et al 1990;Suormala et al 2004;Coelho et al 2008;Miousse et al 2009;Stucki et al 2012). The clinical history of the seven most recently reported patients is not known in detail (Stucki et al 2012).…”

“…The second one presented with self-limited metabolic acidosis in the first days of life and survived without diagnosis until 5 years of age, when he was evaluated because of vomiting and muscle weakness, and eventually diagnosed and treated (Miousse et al 2009). The third patient (Suormala et al 2004) had a complicated history characterized by low gestational age (32 weeks), intracranial hemorrhage, respiratory distress syndrome, necrotizing enterocolitis, and convulsions at birth; neither the age of MMA diagnosis, nor the starting age of the treatment with carnitine, hydroxocobalamin, and protein restriction are known. The treatment led to normalization of EEG traces and reduced urinary MMA.…”

Genetic and genomic systems to study methylmalonic acidemia

“…At least two other genetic entities in the above pathway can be associated with isolated methylmalonic acidemia, cblD (variant 2) deficiency [44] and cblH deficiency [45]. The biochemical and genetic etiology of these disorders has not yet been determined.…”