Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type.

Background: Combined methylmalonic acidemia and homocystinuria cblC type (cblC) is a multisystemic disease with diverse clinical presentations and known genotype-phenotype correlations. This study aims to define and explain the phenotypes and outcomes associated with the MMACHC variant c.1A>G (p.M1V), previously reported in several cases.

Methods: A retrospective review of 54 Chinese patients with cblC carrying the MMACHC c.1A>G variant was conducted. Clinical features, including onset age, initial symptoms, biochemical index and prognosis were analyzed and compared with 100 cblC patients without this variant. The variant's pathogenicity was investigated by in vitro experiments.

Results: Twenty-nine (54 %) of 54 individuals with the c.1A>G variant were diagnosed via newborn screening (NBS) and 23 (79 %) remained asymptomatic. Among 19 symptomatic patients, 12 (63 %) developed symptoms after 1 year of age, with cognitive decline being the most common initial symptom (55 %). Before treatment, all analyzed biochemical indexes except homocysteine showed reduced levels in the c.1A>G group compared to the Control group. Post-treatment, the poor prognosis rate and some metabolite levels in the c.1A>G group were significantly decreased compared to those in the Control group. Western blotting indicated that c.1A>G significantly reduced MMACHC protein expression, and co-immunoprecipitation provided evidence for impaired interaction between the variant MMACHC and methionine synthase (MTR).

Conclusions: The c.1A>G variant in MMACHC is associated with later-onset disease, milder phenotypes and improved clinical outcomes in cblC patients. Functional studies suggest that this variant reduces MMACHC translation efficiency and disrupts its interaction with MTR. Our findings underscore the utility of NBS for early diagnosis and better management in c.1A>G-associated cblC.