Abstract
In this report, we present the case of a 16-month-old patient who was diagnosed with cobalamin G deficiency at 4 months of age via whole exome sequencing by detecting compound heterozygous variants of uncertain significance (VUS) in the MTR gene: (1) c.1283T>A, p.Met428Lys; (2) c.2411T>C, p.Ile804Thr. Before the diagnosis, the initial clinical presentation included failure to thrive, skin hyperpigmentation, hypotonia, seizures, and developmental delay. We initiated the treatment with high-dose parenteral hydroxocobalamin, oral betaine, and folinic acid at 5 months of age (right after receiving WES report). His symptoms, such as skin hyperpigmentation, seizure resolution, developmental delay, and anemia, improved rapidly after the treatment initiation. With treatment, his homocysteine levels declined rapidly and significantly from 117.08 μmol/L at 5 months to 20.23 μmol/L at 5 months and 2 weeks of age. Further, methionine levels increased with treatment from 9.26 μM at 5 months to 14.05 μM at 5 months and 2 weeks of age. The patient is currently receiving intramuscular hydroxocobalamin (2 mg/kg), oral betaine (200 mg/kg), and oral folinic acid (7.5 mg) daily without adverse effects. This case demonstrates the safety and efficacy of early high-dose parenteral hydroxocobalamin, and oral betaine and folinic acid treatment for cobalamin G deficiency. Moreover, given the patient's clinical manifestations, serologic data, and rapid response to therapy, the MTR gene variant previously classified as a VUS should be reclassified as pathogenic and necessitating early diagnosis and treatment.