B. Cobalamin C deficiency
This teenager presented with subacute-onset spastic gait and homocysteine elevation. Homocysteinemia can be acquired or inherited with or without methylmalonic acidemia. His age, normal vitamin and folate levels, and lack of intrinsic factor antibodies suggested an inherited metabolic disorder. Elevation of methylmalonic acid (MMA) narrowed the differential diagnosis.
Methylmalonic acidemia with homocysteinemia is caused by defects in the absorption, transportation, and metabolism of cobalamin.1 Normally, after entering the cell, cobalamin is reduced to cobalamin II through functions of cobalamin F, J, C, and D. Next, cobalamin II is converted to methyl-cobalamin, remethylating homocysteine to methionine. Alternatively, cobalamin II can be converted to adenosyl-cobalamin, a cofactor for methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl-CoA. Blocking this step results in accumulation of L-methylmalonyl-CoA metabolites, which include MMA and methyl citrate acid. Therefore, any defect affecting conversion of cobalamin to cobalamin II will cause simultaneous elevations in homocysteine and MMA, leading to neuronal and endothelial dysfunctions. A cobalamin C (CblC) deficiency (choice B) is most likely. Hereditary spastic paraplegia (choice A) can present with spastic gait, encephalopathy, and seizure but cannot explain the abnormal biochemical results. Cystathionine β-synthase and methionine synthase catalyze conversion of homocysteine to cystathionine and methionine, respectively. Although defects in cystathionine β-synthase (choice C) or cobalamin G or methionine synthase (choice D) can cause homocysteinemia, neither leads to elevated MMA because adenosylcobalamin is unaffected.