Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria

Objective To analyze mutation types, clinical features, and treatment outcomes of cobalamin C(cblC) type combined methylmalonic aciduria and homocystinuria(MMA-HC) and to investigate the relationship of genotypes with clinical phenotypes and outcomes. Methods The clinical data of 16 Chinese children diagnosed with cblC type MMA-HC by gene analysis were retrospectively analyzed. According to the onset age, the patients were classified into early onset(≤1 year) and late onset(1 year). According to the clinical phenotype, the patients were classified into mild, moderate, and severe groups. All the patients were treated with vitamin B12(cyanocobalamin) or hydroxocobalamin, betaine, folate, vitamin B6, and L-carnitine. Results Fifteen patients belonged to the early onset type, including 11 in the severe group and 4 in the moderate group. The remaining one belonged to the late onset type. Seven reported mutations and two novel mutations(c.445_446del TG and c.349Gc) were detected. The c.609GA and c.658_660del AAG were the most common mutations detected in 13(81%) out of 16 patients. The genotype caused by compound heterozygous mutations of these two alleles(c.609 GA/c.658_660del AAG) was the most common in the patients, detected in 4(25%) out of 16 patients. Patients with this genotype had severe microcephaly and eye diseases and these clinical manifestations were not improved after the treatment. The patient with late-onset cblC type MMA-HC had normal clinical phenotypes after treatment. In the 15 early onset patients, the more severe the clinical phenotype, the worse the treatment outcome. Conclusions The cblC type MMA-HC mainly manifests as early onset in China and c.609 G A and c.658_660del AAG are the most common mutations causing this disease. The clinical phenotypes are associated with the outcomes in children with cblC type MMA-HC.