Impact of Early Intervention on the Developmental and Ocular Outcome of Patients With Cobalamin C Deficiency Identified Through Newborn Screening

Despite the implementation of newborn screening (NBS), developmental outcomes in individuals with Cobalamin C (CblC) deficiency remain variable, and ocular manifestations are common. Therapy with hydroxocobalamin (OH-Cbl) is recommended by clinical guidelines, and increasing the dosage may improve outcomes. In this study, we evaluated the developmental and ocular outcomes of individuals with CblC deficiency identified through NBS. We conducted a retrospective analysis of 21 patients with CblC deficiency who were referred after abnormal NBS results and were followed at our center for a median of 9.0 years (0.9-16.1 years). Treatment was initiated at a median age of 9 days (range 4-18 days). All patients received OH-Cbl at a median dosage of 0.16 mg/kg/d (range 0.03-0.36 mg/kg/d) over the follow-up period and followed a regular diet. Thirteen patients presented with neonatal symptoms, but at the last follow-up, 52% of individuals had disease-related symptoms, including seizures in one patient and developmental impairment in 10 cases. Neuropsychological testing was performed in 15 patients and showed cognitive impairment in more than half of them. Ten individuals had ocular manifestations with a median age of onset of 17.5 months (range 3-50 months); of these, nine patients had developmental impairment. 48% of patients were asymptomatic at the last follow-up. Despite early intervention, a substantial proportion of individuals exhibited developmental impairments or ocular manifestations, and neonatal onset appears to be associated with disease severity. Early treatment seems to prevent epilepsy. The potential role of genotype-phenotype correlations, particularly in relation to dosage response, warrants further investigation.