Improved biochemical and neurodevelopmental profiles with high‐dose hydroxocobalamin therapy in cobalamin C defect

Abstract Cobalamin C (Cbl‐C) defect causes methylmalonic acidemia, homocystinuria, intellectual disability and visual impairment, despite treatment adherence. While international guidelines recommend parenteral hydroxocobalamin (OH‐Cbl) as effective treatment, dose adjustments remain unclear. We assessed OH‐Cbl therapy impact on biochemical, neurocognitive and visual outcomes in early‐onset Cbl‐C patients treated with different OH‐Cbl doses over 3 years. Group A ( n = 5), diagnosed via newborn screening (NBS), received high‐dose OH‐Cbl (median 0.55 mg/kg/day); Group B1 ( n = 3), NBS‐diagnosed, received low‐dose OH‐Cbl (median 0.09 mg/kg/day); Group B2 ( n = 12), diagnosed on clinical bases, received low‐dose OH‐Cbl (median 0.06 mg/kg/day). Biochemical analyses revealed better values of homocysteine, methionine and methylmalonic acid in Group A compared to Group B1 ( p < 0.01, p < 0.05 and p < 0.01, respectively) and B2 ( p < 0.001, p < 0.01 and p < 0.001, respectively). Neurodevelopmental assessment showed better outcome in Group A compared to low‐dose treated Groups B1 and B2, especially in Developmental Quotient, Hearing and Speech and Performance subscales without significant differences between Group B2 and Group B1. Maculopathy was detected in 100%, 66% and 83% of patients in the three groups, respectively. This study showed that “high‐dose” OH‐Cbl treatment in NBS‐diagnosed children with severe early‐onset Cbl‐C defect led to a significant improvement in the metabolic profile and in neurocognitive outcome, compared to age‐matched patients treated with a “low‐dose” regimen. Effects on maculopathy seem unaffected by OH‐Cbl dosage. Our findings, although observed in a limited number of patients, may contribute to improve the long‐term outcome of Cbl‐C patients.