Clinical Outcomes and Correlation With Biochemical Control in Hydroxocobalamin-Treated Patients With Early-Onset...

Cobalamin C (cblC) disease is the most common disorder of Vitamin B12 activation. The early-onset form presents within the first few months of life, with some patients identified through newborn screening (NBS). However, despite early detection and optimal treatment, patient outcomes remain poor, with intellectual impairment and progressive visual loss in the majority. We reviewed a cohort of 10 patients with cblC disease, all identified either by NBS or a neonatal clinical presentation. We reviewed their biochemical control and correlated this with clinical progress and treatment. The majority of the cohort (including four asymptomatic patients) was identified through NBS and had genotypes predictive of early-onset disease. Clinical outcomes improved with standard-of-care treatment (hydroxocobalamin, betaine, and folinic acid) but were suboptimal, with both neurocognitive (6/10) and ophthalmological manifestations (10/10) occurring in most patients. One patient died at 5 months of age, and it is unclear whether this was related to cblC disease or not. Across over 250 timepoints from 9 patients, there was minimal correlation between cumulative intramuscular hydroxocobalamin (OHCbl) dose and biomarkers, including methylmalonic acid (r ² = 0.0031) and total homocysteine (r ² = 0.2858) levels. This study provides comprehensive, longitudinal biochemical, and clinical follow-up of patients with cblC disease treated from soon after birth, often presymptomatically. Our findings corroborate previous observations regarding the lack of correlation of current biomarkers, both with disease progression and with standard (< 0.3 mg/kg/day) hydroxocobalamin dosing. Further investigation of the clinical impact of early high-dose OHCbl treatment is needed in larger cohorts of patients.