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

Lili Hao; Yuxin Deng; Si Ding; Wenjuan Qiu; Huiwen Zhang; Lili Liang; Xia Zhan; Ting Chen; Xuefan Gu; Lianshu Han

doi:10.1016/j.ymgme.2025.109182

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

Mol Genet Metab. 2025 Jun 18;145(4):109182. doi: 10.1016/j.ymgme.2025.109182. Online ahead of print.

Authors

Lili Hao¹, Yuxin Deng¹, Si Ding¹, Wenjuan Qiu¹, Huiwen Zhang¹, Lili Liang¹, Xia Zhan¹, Ting Chen¹, Xuefan Gu¹, Lianshu Han²

Affiliations

¹ Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
² Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. Electronic address: hanlianshu@xinhuamed.com.cn.

PMID: 40544542
DOI: 10.1016/j.ymgme.2025.109182

Abstract

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.

Keywords: MMACHC gene; Methylmalonic acidemia; Newborn screening; c.1A>G; cblC.