Biallelic variants in MMACHC results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre‐symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.

An infant with a history of hypotonia, developmental delay, and inadequate nutrition was evaluated. The patient was the offspring of a consanguineous (first cousin) Syrian couple, born at term in Syria after an unremarkable pregnancy. His neonatal course was unremarkable. At the age of 7 months he presented with intermittent diarrhea, fever, and poor feeding. His symptoms progressed, and at 11 months (upon migration to Canada) he was admitted to the hospital for weight loss, decreased urine output, fever, and the loss of skills such as babbling, rolling over, or sitting without support. At the time of admission, he was only taking maternal breast milk.