Project 2- Hydroxocobalamin Study

ABSTRACT – PROJECT 2 (HYDROXOCOBALAMIN DOSE & COBALAMIN C DISEASE) State newborn screening programs, which typically include Cobalamin C Disease, facilitate the early diagnosis and initiation of hydroxocobalamin therapy in newborns with this disorder. Hydroxocobalamin administration reduces the plasma levels of elevated metabolites (methylmalonic acid and homocysteine) and increases the low levels of methionine characteristic of this disorder. However, even with early initiation and good adherence with prescribed hydroxocobalamin therapy, many individuals with Cobalamin C Disease develop long-term complications. These complications may include significant developmental delays and ophthalmologic complications that progress rapidly in infancy leading to blindness. Thus, a major obstacle in the care of individuals with Cobalamin C Disease is the suboptimal management of individuals with this diagnosis. Even with hydroxocobalamin administration, many individuals with Cobalamin C Disease may not have complete normalization of plasma homocysteine, methylmalonic acid, and methionine levels. These findings suggest that suboptimal hydroxocobalamin dosing is one explanation for the poor outcomes in this disorder. Likewise, small case series and case reports suggest that higher dosing of hydroxocobalamin leads to normalization or near- normalization of metabolite level with associated improvement in outcomes. Thus, we hypothesize that hydroxocobalamin dose escalation and intensification will lead to normalization of plasma metabolite levels and, consequently, to associated improvements in long-term developmental and ophthalmologic outcomes. We will test this hypothesis with the following specific aims: 1) To establish correlations between genotype and clinical and biochemical responses to hydroxocobalamin in individuals with Cobalamin C Disease, 2) To determine biochemical response to hydroxocobalamin dose escalation in children and adults with Cobalamin C Disease, and 3) To determine biochemical and phenotypic response to hydroxocobalamin dose intensification in newly diagnosed infants with Cobalamin C Disease. The ROAR consortium proposes a unique NIH extramural- intramural collaboration to complete the proposed studies that would be challenging to perform through any other mechanism. Overall, these proposed studies will establish genotype-phenotype correlations to guide hydroxocobalamin dosing in Cobalamin C Disease and will determine whether high dose regimens lead to improvement in metabolic and clinical phenotypes in this disorder. The resulting data will inform future therapy guidelines for Cobalamin C Disease and larger clinical trials for this disorder. Moreover, our results will provide data that will improve patient access to higher doses of these medications and ultimately, lead to improved outcomes in patients with Cobalamin C Disease.